Open Journal of Psychiatry, 2013, 3, 46-139 OJPsych
http://dx.doi.org/10.4236/ojpsych.2013.31008 Published Online January 2013 (http://www.scirp.org/journal/ojpsych/)
Genomics of schizophrenia and pharmacogenomics of
antipsychotic drugs
Ramón Cacabelos1*, Pablo Cacabelos1, Gjumrakch Aliev1,2
1EuroEspes Biomedical Research Center, Institute for CNS Disorders and Genomic Medicine, EuroEspes Chair of Biotechnology
and Genomics, Camilo José Cela University, Corunna, Spain
2Gally International Biomedical Research Consulting LLC, San Antonio, USA
Received 13 October 2012; revised 15 November 2012; accepted 24 November 2012
ABSTRACT
Antipsychotic drugs are the neuroleptics currently
used in the treatment of schizophrenia (SCZ) and
psychotic disorders. SCZ has a heritability estimated
at 70% - 90%; and pharmacogenomics accounts for
60% - 90% variability in the pharmacokinetics and
pharmacodynamics of psychotropic drugs. Personal-
ized therapeutics based on individual genomic pro-
files in SCZ entails the characterization of 5 types of
gene clusters and their related metabolomic profiles:
1) genes associated with disease pathogenesis; 2)
genes associated with the mechanism of action of
drugs; 3) genes associated with drug metabolism
(phase I and II reactions); 4) genes associated with
drug transporters; and 5) pleiotropic genes involved
in multifaceted cascades and metabolic reactions.
Genetic studies in SCZ have revealed the presence of
chromosome anomalies, copy number variants, mul-
tiple single-nucleotide polymorphisms of susceptibil-
ity distributed across the human genome, aberrant
single-nucleotide polymorphisms in microRNA genes,
mitochondrial DNA mutations, and epigenetic phe-
nomena. Pharmacogenetic studies of psychotropic
drug response have focused on determining the rela-
tionship between variation in specific candidate genes
and the positive and adverse effects of drug treatment.
Approximately 18% of neuroleptics are major sub-
strates of CYP1A2 enzymes, 40% of CYP2D6, and
23% of CYP3A4. About 10% - 20% of Western
populations are defective in genes of the CYP super-
family. Only 26% of Southern Europeans are pure
extensive metabolizers for the trigenic cluster inte-
grated by the CYP2D6 + CYP2C19 + CYP2C9 genes.
Efficacy and safety issues in the pharmacological
treatment of SCZ are directly linked to genetic clus-
ters involved in the pharmacogenomics of antipsy-
chotic drugs and also to environmental factors. Con-
sequently, the incorporation of pharmacogenomic
procedures both to drugs under development and
drugs on the market would help to optimize thera-
peutics in SCZ and other central nervous system dis-
orders.
Keywords: Genomics; Antipsychotic Drugs;
Schizophrenia
1. INTRODUCTION
Central nervous system (CNS) disorders are the third
greatest problem of health in developed countries, repre-
senting 10% - 15% of deaths after cardiovascular disor-
ders (25%) and cancer (20%). CNS disorders pose sev-
eral challenges to our society and the scientific commu-
nity: 1) they represent an epidemiological problem and a
socio-economic, psychological and family burden; 2)
most of them have an obscure/complex pathogenesis; 3)
their diagnosis is not easy and lacks specific biomarkers;
and 4) their treatment is difficult and inefficient. In terms
of economic burden, approximately 10% - 20% of direct
costs are associated with their pharmacological treatment,
with a gradual increase in parallel with the severity of the
disease [1,2].
Approximately 127 million Europeans suffer brain
disorders. The total annual cost of brain disorders in
Europe is about €386 billion, with €135 billion in direct
medical expenditures (€78 billion, inpatients; €45 billion,
outpatients; €13 billion, pharmacological treatment),
€179 billion in indirect costs (lost workdays, loss of
productivity, permanent disability), and €72 billion in
direct non-medical costs. Mental disorders represent
€240 billion (62% of the total cost, excluding dementia),
followed by neurological diseases (€84 billion, 22%) [3].
Common features in CNS disorders include the fol-
lowing: 1) polygenic/complex disorders in which genetic,
epigenetic and environmental factors are involved; 2)
deterioration of higher activities of the CNS; 3) multi-
factorial dysfunctions in several metabolomic networks
leading to functional damage to specific brain circuits;
*Corresponding author.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 47
and 4) accumulation of toxic proteins in the nervous tis-
sue in cases of neurodegeneration [1,2].
Our understanding of the pathophysiology of CNS
disorders has advanced dramatically during the last 30
years, especially in terms of their molecular pathogenesis
and genetics. Drug treatment has also made remarkable
strides, with the introduction of many new drugs; how-
ever, improvement in terms of clinical outcome has
fallen short of expectations, with up to one third of pa-
tients continuing to experience clinical relapse or unac-
ceptable medication-related side-effects in spite of efforts
to identify optimal treatment regimens. Potential reasons
to explain this historical setback might be that: 1) the
molecular pathology of brain disorders is still poorly
understood; 2) drug targets are inappropriate, not fitting
into the real etiology of the disease; 3) most treatments
are symptomatic, but not anti-pathogenic; 4) the genetic
component of CNS disorders is poorly defined; and 5)
the understanding of genome-drug interactions is very
limited [2,4-6].
The pharmacological management of CNS disorders is
an issue of special concern due to the polymedication
required to modulate the symptomatic complexity of
brain disorders. The introduction of novel procedures
into an integral genomic medicine protocol in CNS dis-
orders is an imperative requirement for clinical practice
and drug development in order to improve diagnostic
accuracy (disease-specific biomarkers) and to optimize
therapeutics (pharmacogenomics) [7-12]. A growing
body of fresh knowledge on the pathogenesis of CNS
disorders, together with data on neurogenomics and
pharmacogenomics, is emerging in recent times. The
incorporation of this new armamentarium of molecular
pathology and genomic medicine to daily medical prac-
tice, together with educational programs for the correct
use of drugs, must help to: 1) understand brain patho-
genesis; 2) establish an early diagnosis; and 3) optimize
therapeutics either as a preventive strategy or as a formal
symptomatic treatment [2,5,6,13,14].
Schizophrenia (SCZ) is a typical paradigm of mental
disorder with a prevalence of 1% and a high socioeco-
nomic impact in our society. SCZ and related disorders
are highly heritable but cannot be explained by currently
known genetic risk factors. SCZ has a heritability esti-
mated at 70% - 90% [1,15-17]. Several neurobiological
hypotheses have been postulated as responsible for SCZ
pathogenesis: polygenic/multifactorial genomic defects,
intrauterine and perinatal environment-genome interac-
tions, neurodevelopmental defects, dopaminergic, cho-
linergic, serotonergic, GABAergic, neuropeptidergic and
glutamatergic/NMDA dysfunctions, seasonal infection,
neuroimmune dysfunction, and epigenetic dysregula-
tion.The dopamine hypothesis of SCZ has been one of
the most enduring ideas in psychiatry. Initially, the em-
phasis was on the role of hyperdopaminergia in the eti-
ology of SCZ, but it was subsequently reconceptualized
to specify subcortical hyperdopaminergia with prefrontal
hypodopaminergia [18]. Carlsson’s hypothesis postulates
that the positive and negative symptoms of SCZ are due
to failure of mesolimbic and mesocortical projections
consequent on hypofunction of the glutamate N-methyl-
D-aspartate (NMDA) receptor. The emergence of posi-
tive symptoms (hallucinations), and synapse regression
involves molecules such as neuregulin and its receptor
ErbB4, which have been implicated in SCZ [19]. While
multiple theories have been put forth regarding the origin
of SCZ, by far the vast majority of evidence points to the
neurodevelopmental model in which developmental in-
sults as early as late first or early second trimester lead to
the activation of pathologic neural circuits during ado-
lescence or young adulthood, leading to the emergence
of positive or negative symptoms. There is evidence
from brain pathology (enlargement of the cerebroven-
tricular system, changes in gray and white matters, and
abnormal laminar organization), genetics (changes in the
normal expression of proteins involved in early migra-
tion of neurons and glia, cell proliferation, axonal out-
growth, synaptogenesis, and apoptosis), environmental
factors (increased frequency of obstetric complications
and increased rates of schizophrenic births due to prena-
tal viral or bacterial infections), and gene-environmental
interactions (a disproportionate number of SCZ candi-
date genes are regulated by hypoxia, microdeletions and
microduplications, the overrepresentation of pathogen-
related genes among SCZ candidate genes) in support of
the neurodevelopmental model [20]. Dean [21] reviewed
evidence to assess the hypothesis that SCZ is a hu-
man-specific disorder associated with the need for highly
complex CNS development. Changes in the size of the
frontal lobe, increases in numbers of specific cell types,
changes in gene expression and changes in genome se-
quence all seem to be involved in the evolution of the
human CNS. Human-specific changes in CNS develop-
ment are wide-ranging. The modification in CNS struc-
ture and function that has resulted from these changes
affects many pathways and behaviors that also appear to
be affected in subjects with SCZ. Therefore, there is evi-
dence to support the hypothesis that SCZ is a disease that
develops due to derangements to human-specific CNS
functions that have emerged since our species diverged
from non-human primates.
Antipsychotic drugs (neuroleptics) represent the pri-
mary pharmacological treatment for schizophrenia and
psychotic disorders worldwide. The proportion of treat-
ment-resistant patients is estimated to be 20% to 40%,
and the treatment of patients with schizophrenia who fail
to respond to antipsychotics is a major challenge in psy-
chiatry [22]. Studies reported during the past 20 years

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 48
2.2. Genes Associated with the Mechanism of
Action of Drugs
have demonstrated that the efficacy and safety of anti-
psychotics are closely related to the pharmacogenomic
profiles of schizophrenic patients [1,17,22]. Most genes associated with the mechanism of action of
CNS drugs encode receptors, enzymes, and neurotrans-
mitters (Tables 1 an d 2) on which psychotropic drugs act
as ligands (agonists, antagonists), enzyme modulators
(substrates, inhibitors, inducers) or neurotransmitter re-
gulators (releasers, reuptake inhibitors) [25].
2. GENES INVOLVED IN
PHARMACOGENOMICS
The genes involved in the pharmacogenomic response to
drugs in CNS disorders may fall into five major catego-
ries: 1) genes associated with CNS pathogenesis (dis-
ease-specific genes); 2) genes associated with the
mechanism of action of drugs; 3) genes associated with
drug metabolism; 4) genes associated with drug trans-
porters; and 5) pleiotropic genes involved in multifaceted
cascades and metabolic reactions [2]. The therapeutic
outcome (efficacy and safety) is the result of the inter-
play of drugs with these different categories of gene
products and epigenetic factors to reverse or modify the
phenotypic expression of a given disease [23]. Pharma-
cogenomics accounts for 30% - 90% variability in phar-
macokinetics and pharmacodynamics.
2.3. Genes Involved in Drug Metabolism
Drug metabolism includes phase I reactions (i.e. oxida-
tion, reduction, hydrolysis) and phase II conjugation re-
actions (i.e. acetylation, glucuronidation, sulphation,
methylation). The principal enzymes with polymorphic
variants involved in phase I reactions are the following:
Cytochrome P450 monooxygenases (CYP3A4/5/7, CYP-
2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6,
CYP2A6, CYP1B1, CYP1A1/2), epoxide hydrolase,
esterases, NQO1 (NADPH-quinone oxidoreductase),
DPD (dihydropyrimidine dehydrogenase), ADH (alcohol
dehydrogenase), and ALDH (aldehyde dehydrogenase);
and major enzymes involved in phase II reactions in-
clude UGTs (uridine 5’-triphosphate glucuronosyl trans-
ferases), TPMT (thiopurine methyltransferase), COMT
(catechol-O-methyltransferase), HMT (histamine methyl-
transferase), STs (sulfotransferases), GST-A (glutathione
S-transferase A), GST-P, GST-T, GST-M, NAT1 (N-ace-
tyl transferase 1), NAT2, and others. Among these en-
zymes, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5
are the most relevant in the pharmacogenetics of CNS
drugs [14,25] (Tabl e 2 ). Approximately, 18% of neuro-
leptics are major substrates of CYP1A2 enzymes, 40%
2.1. Pathogenic Genes
Over 6000 genes distributed across the human genome
have been screened for associations with CNS disorders
during the past 30 years [1,24]. Studies of many candi-
date genes potentially associated with a particular CNS
disorder could not be replicated in different settings, co-
horts, and geographical contexts due to methodological
problems, sample selection and multi-ethnic genetic
variation. In the case of SCZ and related disorders, over
200 genes have been associated with psychotic disorders
[1,7] (Figure 1, Table 1).
Figure 1. Distribution of genes potentially associated with psychosis and dementia in the
human genome.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 49
Table 1. Genes potentially associated with schizophrenia and psychotic disorders.
Symbol Name Locus SZC-Related SNPsOther Diseases
ABCA7
ATP-binding cassette,
sub-family A (ABC1),
member 7
19p13.3
ABCA13
ATP-binding cassette,
sub-family A (ABC1),
member 13
7p12.3
ABCB1
ATP-binding cassette,
sub-family A (ABC1),
member 1
9q31.1 rs3858075
Atherosclerosis; Cerebral amyloid angiopathy; Colorectal cancer;
Colorectal neoplasms; Coronary artery disease; Coronary disease;
Dyslipidemias; Familial hypercholesterolemia; High density
lipoprotein deficiency (type 1); High density lipoprotein deficiency
(type 2); Hyperalphalipoproteinemia;
Hypercholesterolemia; Hyperlipidemia; Kidney diseases;
Tangier disease
ACE
Angiotensin I converting
enzyme (peptidyl-dipeptidase
A) 1
17q23.3
Alzheimer disease; Anxiety disorders; Cardiovascular diseases;
Hemorrhagic stroke; Dementia; Depression; Diabetes mellitus;
Diabetic nephropathy; Hyperlipidemias; Hypertension;
Hypotension; IgA glomerulonephritis; IgA nephropathy; Ischemic
stroke; Major depressive disorder; Meningococcal disease;
Myocardial infarction; Myophosphorylase deficiency; Preterm
cardiorespiratory disease; Renal tubular dysgenesis; Severe acute
respiratory syndrome; Stroke; Susceptibility to microvascular
complications of diabetes I; Vascular dementia
ACSL6 Acyl-CoA synthetase
long-chain family member 6 5q31 rs11743803
Acute eosinophilic leukemia; Acute myelogenous leukemia; Acute
myelogenous leukemia; Myelodysplastic syndrome
ADRA1A Adrenergic,
alpha-1A-, receptor 8p21.2
Attention-deficit hyperactivity disorder; Hypertension
ADRA2A Adrenergic alpha-2A,
receptor 10q24-q26 rs1800544
Diarrhea-predominant irritable bowel syndrome; Response to
methylphenidate treatment in Korean subjects with attention deficit
hyperactivity disorder; Obesity; Predisposition to
tobacco smoking
ADSS Adenylosuccinate synthase 1cen-q12 rs227061;
rs3102460
Joubert syndrome-3
AHI1 Abelson helper integration
site 1 6q23.3 rs7750586; rs911507
AKT1 v-akt murine thymoma viral
oncogene homolog 1 14q32.32 rs3803300
Breast cancer, somatic; Colorectal cancer, somatic; Ovarian cancer,
somatic
ALDH1A2 Aldehyde dehydrogenase 1
family, member A2 15q21.3 rs4646642-rs4646580
ALDH3B1 Aldehyde dehydrogenase 3
family, member B1 11q13
AP3M1 Adaptor-related protein
complex 3, mu 1 subunit 10q22.2 rs6688
APOE Apolipoprotein E 19q13.2
Age-related macular degeneration; Age-related macular
degeneration 1; Alzheimer disease; Amyloidosis;
APOE5-associated hyperlipoproteinemia and atherosclerosis;
APOE7-associated type III hyperlipoproteinemia;
Apolipoproteinemia E1; Arteriosclerosis; Asthma; Atherosclerosis;
Autosomal dominant type III hyperlipoproteinemia; Autosomal
recessive hyperlipoproteinemia; Autosomal recessive type III
hyperlipoproteinemia associated with APOE deficiency;
Cardiovascular disease; Carotid stenosis; Cerebrovascular disease;
Coronary arteriosclerosis; Craniocerebral trauma; Drug-induced
liver injury; Dysbetalipoproteinemia; Dysbetalipoproteinemia due
to APOE2; Dyslipidemias; Familial dysbetalipoproteinemias;
Macular degeneration; Hypertriglyceridemia; Ischemic
cerebrovascular disease; Ischemic heart disease; Ischemic stroke;
Lipoprotein glomerulopathy; Lung neoplasms;
Hyperlipoproteinemia (type II); Hyperlipoproteinemia (type III);

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 50
Continued
Hyperlipoproteinemias; Metabolic syndrome; Multiple
sclerosis; Myocardial infarction; Myocardial ischemia;
Neurodegenerative diseases; Psoriasis; Sea-blue histiocyte
syndrome; Type III hypercholesterolemia and
hypertriglyceridemia; Type III hyperlipoproteinemia; Type III
hyperlipoproteinemia associated with APOE deficiency; Type
III hyperlipoproteinemia associated with APOE Leiden; Type
III hyperlipoproteinemia associated with APOE2; Type III
hyperlipoproteinemia associated with APOE2-Fukuoka; Type
III hyperlipoproteinemia associated with APOE4; Type III
hyperlipoproteinemia due to APOE1-Harrisburg; Type III
hyperlipoproteinemia due to APOE4-Philadelphia; Type III
hyperliporpoteinemia due to APOE2-Christchurch; Type V
hyperlipoproteinemia; Vascular dementia; Vascular disease
APOL1 Apolipoprotein L, 1 22q13.1
APOL2 Apolipoprotein l, 2 22q12
APOL4 Apolipoprotein l, 4 22q11.2-q13.2
ARRB2 Arrestin, beta 2 17p13 rs1045280
Ser280Ser
ARVCF
Armadillo repeat gene
deleted in velocardiofacial
syndrome
22q11.21
ATM Ataxia telangiectasia
Mutated 11q22-q23 rs664143 rs227061
AVPR1A Arginine vasopressin
receptor 1A 12q14-q15
AVPR1B Arginine vasopressin
receptor 1B 1q32
BDNF Brain-derived
neurotrophic factor 11p13 rs6265 Val66Met C270T
Aniridia; Anorexia nervosa; Bipolar disorder; Bulimia
nervosa; Congenital central hypoventilation syndrome;
Depressive disorder; Genitourinary anomalies, Lithium
response; Major depressive disorder; Memory impairment;
Mental retardation; Methadone response; Obesity;
Obsessive-compulsive disorder; Parkinson’s disease;
Protection against obsessive-compulsive disorder; Tardive
dyskinesia; WAGR syndrome; Wilms’ tumor
BIK BCL2-interacting killer
(apoptosis-inducing) 22q13.31 rs926328; rs2235316
BLOC1S3
Biogenesis of lysosomal
organelles complex-1,
subunit 3
19q13.32
BRD1 Bromodomain containing
1 22q13.33
C3 Complement component 3 19p13.3-p13.2 Age-related macular degeneration 9; C3 deficiency;
Susceptibility to atypical hemolytic uremic syndrome 5
C4B Complement component
4B (Chido blood group) 6p21.3 C4 deficiency
C6orf217 Chromosome 6 open
reading frame 217 6q23.3 rs1475069
C10orf26,
OPAL1 Chromosome 10 open reading frame 26 10q24.32
C22DDEL
S
Chromosome 22q11.2
deletion syndrome, distal 22q11.2
CACNA1C
Calcium channel,
voltage-dependent, L type,
alpha 1C subunit
12p13.3 rs1006737;
rs22512119
CALR Calreticulin 19p13.3-p13.2
CCKAR Cholecystokinin A
receptor 4p15.1-p15.2 rs1800857; 779T/C

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 51
Continued
CDC42SE2 CDC42 small effector 2 5q31.1
CFB Complement factor B 6p21.3 Reduced risk of age-related macular degeneration; Susceptibility to
atypical hemolytic uremic syndrome 4
CHAT Choline O-acetyltransferase 10q11.2
Alzheimer disease; Congenital myasthenic syndrome associated with
episodic apnea; Myasthenic syndrome; Neurodegenerative
diseases; Neurotoxicity syndromes; Parkinson’s disease (secondary);
Peripheral nervous system diseases
CHGA Chromogranin A (parathyroid
secretory protein 1) 14q32
CHGB Chromogranin B
(secretogranin 1) 20pter-p12
CHI3L1 Chitinase 3-like 1 (cartilage
glycoprotein-39) 1q32.1
Effect of variation in CHI3L1 on serum YKL-40 level, risk of
asthma, and lung function; Susceptibility to asthma-related traits 7
CHRFAM7
A
CHRNA7 (cholinergic
receptor, nicotinic, alpha 7,
exons 5 - 10) and FAM7A
(family with sequence similarity
7A, exons A-E) fusion
15q13.1
CHRNA2 Cholinergic receptor, nicotinic,
alpha 2 (neuronal) 8p21 Nocturnal frontal lobe epilepsy type 4
CHRNA6 Cholinergic receptor, nicotinic,
alpha 6 8p11.21
CHRNA7 Cholinergic receptor, nicotinic,
alpha 7 15q14 rs3087454
CHRNB3 Cholinergic receptor, nicotinic,
beta 3 8p11.2
CLDN5 Claudin 5 22q11.21
CLINT1 Clathrin interactor 1 5q33.3
CLOCK Clock homolog (mouse) 4q12
CLU Clusterin 8p21-p12 rs11136000
CMYA5 Cardiomyopathy associated 5 5q14.1 rs10043986;
rs4704591
CNP 2’,3’-cyclic nucleotide 3’
phosphodiesterase 17q21
CNR1 Cannabinoid receptor 1 (brain) 6q14-q15
Alzheimer disease; Central nervous system diseases; Cocaine-related
disorders; Muscle spasticity; Neurodegenerative diseases;
Neurotoxicity syndromes; Substance withdrawal syndrome
CNR2 Cannabinoid receptor 2
(macrophage) 1p36.11
CNTNAP2 Contactin associated
protein-like 2 7q35
Cortical dysplasia focal epilepsy syndrome; Autism (susceptibility);
Pitt-Hopkins-like syndrome
Anxiety disorders; Autistic disorder; Bipolar disorder; Depressive
disorder; DiGeorge syndrome; Migraine; Mood disorders; Nervous
system diseases; Panic disorder; Obsessive-compulsive disorder;
Parkinson’s disease; Prostatic neoplasms
COMT Catechol-O-methyltransferase 22q11.21
rs4680; rs6267;
rs737865
rs7378-rs4680-
rs165599
rs2075507
rs362204 Susceptibility to panic disorder
CPLX2 Complexin 2 5q35.2 rs3822674
CRP C-reactive protein,
pentraxin-related 1q21-q23
Atherosclerosis; Cardiovascular disease; Cerebrovascular disease;
Coronary disease; Diabetes mellitus (type 2); Heart diseases; Heart
failure; Heart injuries; Hepatocellular carcinoma; Inflammation; Lung
neoplasms; Lupus erythematosus; Malaria; Pasteurellaceae
infections; Stroke; Systemic lupus erythematosus; Thrombosis
CSF2RA Colony stimulating factor 2
receptor, alpha, low-affinity
(granulocyte-macrophage)
Xp22.32 and
Yp11.3 Acute M2 type myeloid leukemia; Pulmonary alveolar proteinosis

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 52
Continued
CSF2RB
Colony stimulating factor
2 receptor, beta,
low-affinity
(granulocyte-macrophage)
22q13.1 Pulmonary alveolar proteinosis
CSMD1 KIAA1890 Cub and Sushi multiple
domains 1
8p23.2
CTL4 cytotoxic
T-lymphocyte-associated
protein 4
2q33 rs231779;
rs16840252
CTSK cathepsin K 1q21 Pycnodysostosis
CYBB Cytochrome b-245, beta
polypeptide Xp21.1
CYP1A2 Cytochrome P450, family 1,
subfamily A, polypeptide 2 15q24.1
Experimental liver cirrhosis; Experimental liver neoplasms;
Experimental neoplasms; Gastric adenocarcinoma; Gastrointestinal
neoplasms; Hepatocellular carcinoma; Leflunomide-induced
toxicity; Methemoglobinemia; Myocardial infarction; Liver
diseases; Neoplasms; Susceptibility to tobacco addiction; Tardive
dyskinesia; Tobacco use disorder
CYP3A4/5 Cytochrome P450, family 3,
subfamily A, polypeptide 4/5 7q21.1
Acute hypoxia; Acute lymphoblastic leukemia; Acute myeloid
leukemia; Age-related metabolism variation; Alcoholism; Allergic
rhinitis; Alveolar echinococcosis; Antiplatelet drug resistance;
Antiretroviral-antineoplastic drug interactions; Atherosclerosis;
Azoospermia; Balkan endemic nephropathy; Barrett’s metaplasia;
Benign prostate hyperplasia; Bile acid metabolism; Bladder cancer;
Blood pressure; Brain tumors; Breast cancer; Breast neoplasms;
Cancer; Celiac disease; Cerebrotendinous xanthomatosis;
Cholestasis; Cholesterol homeostasis; Chronic hepatitis C;
Cirrhosis; Colon adenoma; Colorectal cancer; Colorectal liver
metastases; Crohn’s disease; Cushing’s syndrome; Cystic fibrosis;
Depression; Depressive disorder; Diabetes mellitus (type 2);
Diffuse panbronchiolitis; Drug-induced liver injury; Drug-virus
interaction; Ehrlichiosis; Endometrial cancer; Epilepsy; Erectile
dysfunction; Esophageal squamous cell carcinoma; Food-drug
interactions; Gastric tumors; Gingival hyperplasia;
Glucocorticoid-induced hypertension in children with acute
lymphoblastic leukemia; Headache; Helicobacter pylori;
Hepatic steatosis; Hepatitis; Hepatitis B infection; Hepatocellular
tumors; Hodgkin’s disease; Hodgkin’s lymphoma; Hypertension;
Hypothermia; Inflammatory bowel diseases; Lactobacillus
rhamnosus; Leukemia; Liver cancer; Liver diseases; Liver
neoplasms; Lung cancer; Lung neoplasms; Lymphocytes; Malaria;
Menopause; Menstruation; Metabolic syndrome; Metabolic
syndrome X; Migraine; Multiple myeloma; Myocardial infarction;
Myocardial ischemia; Nasopharyngeal carcinoma; Neuropathic
pain; Non-alcoholic fatty liver disease; Non-small cell lung cancer;
Non-small cell lung carcinoma; Onychomycosis; Osteomalacia;
Osteonecrosis; Osteosarcoma; Ovarian cancer; Ovarian neoplasms;
Oxidative stress; Parkinson’s disease; Porphyrias; Precocious
puberty; Pregnancy; Pregnancy complications; Primary biliary
cirrhosis; Proctitis; Prostate cancer; Prostatic hyperplasia; Prostatic
neoplasms; QT interval prolongation; Renal cancer; Renal cell
carcinoma; Rhabdomyolysis; Schizophrenia; Squamous cell
carcinoma of the larynx and hypopharynx; Stroke; T-cell
lymphomas; Testicular germ cell cancer; Thalassemia; Torsades de
pointes; Tuberculosis; Veno-occlusive disease; Venous
thromboembolism; Venous thrombosis
DAAM2 Dishevelled associated
activator of morphogenesis 2 6p21.2

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 53
Continued
DAO D-amino-acid oxidase 12q24
rs2111902;
rs3741775;
rs3918346;
rs4623951;
rs3918347-rs4964770;
rs3825251-rs3918347-;
rs4964770
DAOA D-amino acid oxidase
activator
13q34 rs3916971;
rs778293;
rs2391191 (M15);
rs778293;
rs3918342
DBH Dopamine beta-hydroxylase
(dopamine
beta-monooxygenase)
9q34 rs1108580
DDR1 Discoidin domain receptor
tyrosine kinase 1 6p21.3 rs4532
Attention-deficit hyperactivity disorder; Autistic disorder;
Bipolar disorder; Mental disorders; Nicotine dependence
DGCR2 DiGeorge syndrome
critical region gene 2 22q11.21 rs2073776
DGCR6 DiGeorge syndrome
critical region gene 6 22q11
DISC1 Disrupted in schizophrenia 1 1q42.1
rs3737597;
rs821616;
rs6675281;
rs821597
Susceptibility to schizoaffective disorder
DISC2 Disrupted in schizophrenia 2
(non-protein coding) 1q42.1 Association of lipid-lowering response to statins in combined study populations
DKK4 Dickkopf homolog
4
(Xenopus laevis) 8p11.2-p11.1
DNMT3B DNA
(cytosine-5-)-
methyltransferase 3 beta
20q11.2 rs6119954;
rs2424908
DPYSL2 Dihydropyrimidinase-like 2 8p22-p21
DRD1 Dopamine receptor D1 5q35.1
DRD2 Dopamine receptor D2 11q23
rs1799732;
rs2283265;
rs12364283;
rs1076560;
rs1079597 (Taql-B);
rs6277;
rs1801028;
rs6275; rs6277;
rs11608185
Alcoholism; Myoclonic dystonia; Myoclonus-dystonia
syndrome; Obesity; Parkinson’s disease; Substance
withdrawal syndrome; Tardive dyskinesia
DRD3 Dopamine receptor D3 3q13.3 rs6280
Autistic disorder; Hereditary essential tremor 1; Nicotine
addiction; Parkinson’s disease; Susceptibility to essential
tremor; Tardive dyskinesia
DRD4 Dopamine receptor D4 11p15.5
rs1805186;
120-bp TR;
rs1800955;
rs4646983;
rs4646984
Attention-deficit hyperactivity disorder; Autonomic nervous
system dysfunction; Novelty-seeking personality trait;
Parkinson’s disease; Personality disorders; Protection
against Parkinson’s disease; Psychotic disorders; Tobacco
use disorder
DRD5 Dopamine receptor D5 4p16.1 (CT/GT/GA)n
(CA)n
Primary benign blepharospasm; Primary cervical
dystonia; Susceptibility to attention-deficit hyperactivit
y
disorder

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 54
Continued
DTNBP1 Dystrobrevin binding protein
1 6p22.3
rs104893945;
rs2619522;
rs7758659;
rs1047631;
rs1474605;
rs2005976;
rs2619539;
rs760666;
rs2619528;
rs2619538;
rs875462;
rs3213207;
rs760761;
rs1011313;
rs1018381;
rs2619538
(SNPA);
rs3213207
(P1635)
Bipolar disorder; Major depressive disorder; Hermansky-Pudlak
syndrome; Hermansky-Pudlak syndrome 7
EGF Epidermal growth factor 4q25 Renal hypomagnesemia 4
ERBB3
v-erb-b2 erythroblastic
leukemia viral oncogene
homolog 3 (avian)
12q13 rs773123 Lethal congenital contractural syndrome 2
ERBB4
v-erb-a erythroblastic
leukemia viral oncogene
homolog 4 (avian)
2q33.3-q34
ESR1 Estrogen receptor 1 6q25.1
FABP7 Fatty acid binding protein 7,
brain 6q22-q23
FADS2 Fatty acid desaturase 2 11q12.2
FAS Fas (TNF receptor
superfamily, member 6) 10q24.1
Association of IFIH1 and other autoimmunity risk alleles with
selective IgA deficiency; Autoimmune lymphoproliferative
syndrome; Autoimmune lymphoproliferative syndrome, type IA;
Burn scar-related somatic squamous cell carcinoma
FGF1 Fibroblast growth factor 1
(acidic) 5q31
FGF17 Fibroblast growth factor 17 8p21
FGFR1 Fibroblast growth factor
receptor 1 8p12
FMO3 Flavin containing
monooxygenase 3 1q24.3 Familial adenomatous polyposis; Trimethylaminuria
FOLH1
Folate hydrolase
(prostate-specific membrane
antigen) 1
11p11.2
FOXP2 Forkhead box P2 7q31 Speech-language disorder-1
FTO Fat mass and obesity
associated 16q12.2 rs9939609
FXYD2 FXYD domain containing ion
transport regulator 2 11q23 Renal hypomagnesemia-2
FXYD6 FXYD domain containing ion
transport regulator 6 11q23.3
rs11544201
rs10790212-
rs11544201
FYN FYN oncogene related to
SRC, FGR, YES 6q21 rs6916861; rs3730353
FZD3 Frizzled homolog 3
(Drosophila) 8p21

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 55
Continued
GABBR1 Gamma-aminobutyric acid
(GABA) B receptor, 1 6p21.31
GABRB1 Gamma-aminobutyric acid
(GABA) A receptor, beta 1 4p12
GABRB2 Gamma-aminobutyric acid
(GABA) A receptor, beta 2 5q34 rs1816072
GABRG2 Gamma-aminobutyric acid
(GABA) A receptor, gamma 2 5q34
Childhood absence epilepsy; Childhood absence epilepsy 2; Familial
febrile convulsions 8; Generalized epilepsy with febrile seizures plus;
Generalized epilepsy with febrile seizures plus, type 3; Severe
myoclonic epilepsy of infancy; Susceptibility to childhood absence
epilepsy 2
GAD1 Glutamate decarboxylase 1
(brain, 67 kDa) 2q31 Autosomal recessive symmetric spastic cerebral palsy
GAD2
Glutamate decarboxylase 2
(pancreatic islets and brain, 65
kDa)
10p11.23
GC Group-specific component
(vitamin D binding protein) 4q12-q13 Susceptibility to Graves’ disease 3
GCLM Glutamate-cysteine ligase,
modifier subunit 1p22.1 Susceptibility to myocardial infarction
GJA8 Gap junction protein, alpha 8,
50 kDa 1q21.1
Cataract-microcornea syndrome; Nuclear progressive cataract;
Nuclear pulverulent cataract; Zonular pulverulent cataract 1
GLS Glutaminase 2q32-q34
GLUL Glutamate-ammonia ligase 1q31
GNB1L
Guanine nucleotide binding
protein (G protein), beta
polypeptide 1-like
22q11.2
GRIA1 Glutamate receptor,
ionotropic, AMPA 1 5q31.1
GRIA4 Glutamate receptor,
ionotrophic, AMPA 4 11q22
GRID1 Glutamate receptor,
ionotropic, delta 1 10q22
rs3814614;
rs10749535;
rs11201985
GRIK3 Glutamate receptor,
ionotropic, kainate 3 1p34-p33 rs6691840
GRIK4 Glutamate receptor,
ionotropic, kainate 4 11q22.3
rs4935752;
rs6589846;
rs4430518
Bipolar disorder; Depression
GRIK5 Glutamate receptor,
ionotropic, kainate 5 19q13.2
GRIN1 Glutamate receptor, iono-
tropic, N-methyl D-aspartate 1 9q34.3
12p12 rs1019385
GRIN2B
Glutamate receptor,
ionotropic, N-methyl
D-aspartate 2B rs7301328
GRIN2D Glutamate receptor,
ionotropic, N-methyl
D-aspartate 2D
19q13.1-qter
GRM3 Glutamate receptor,
metabotropic 3 7q21.1-q21.2
GRM4 Glutamate receptor,
metabotropic 4 6p21.3

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 56
Continued
GRM7 Glutamate receptor,
metabotropic 7 3p26.1-p25.1
rs12491620;
rs1450099
GPR109A G protein-coupled receptor
109A 12q24.31
GPR109B G protein-coupled receptor
109B 12q24.31
GSK3B Glycogen synthase kinase 3 beta 3q13.3
(CAA)n repeat
polymorphisms;
-1727 A/T
Alzheimer disease; Bipolar disorder; Cancer; Colonic neoplasms;
Colorectal neoplasms; Diabetes (type 2); Diabetes mellitus;
Depression; Insulin resistance; Lithium sensitivity; Major depression;
Myeloid/lymphoid or mixed lineage leukemia; Neurodegenerative
diseases; Parkinsonian disorders; Tauopathy
GSTM1 Glutathione S-transferase mu 1 1p13.3 GSTM1*0
Acute lymphoblastic leukemia; Acute myeloid leukemia; Acute
promyelocytic leukemia; Adverse drug reactions to azathioprine;
Aflatoxin-related hepatocarcinogenesis; Aplastic anemia; Autism;
Autistic disorder; Azathioprine adverse effects; Benzene toxicity;
Basal cell nervous syndrome; Basal cell carcinoma; Bladder cancer;
Bleomycin moderate toxicity; Breast cancer; Busulfan
pharmacokinetics; Carbamazepine-induced mild hepatotoxicity;
Carcinogen toxicity; Colorectal cancer; Colorectal neoplasms;
Coronary artery disease; Cytochrome P450 1A1 gene transcription;
Diabetes mellitus (type 2); DNA damage after exposure to
hydroquinone; Diabetic nephropathy; GSTM1 methylation; Head and
neck neoplasms; Hepatocellular carcinoma; Leukemia;
Hydroquinone-induced DNA damage; High inducibility of
cytochrome P450 1A1 gene transcription; Liver cancer; Liver
neoplasms; Lung cancer; Lung neoplasms; Lymphoblastic leukemia;
Mesothelioma; Methotrexate toxicity; Myelodisplastic syndrome;
Myeloid leukemia; Prostate cancer; Prostatic neoplasms; Raynaud’s
disease; Responses to environmental and industrial carcinogens;
Second primary neoplasms; Skin diseases; Systemic lupus
erythematosus; Tacrine-induced hepatotoxicity; Testicular
neoplasms; Thimerosal sensitization; Urinary bladder neoplasms;
Troglitazone-induced liver failure
GSTP1 Glutathione S-transferase pi 1 11q13
GSTT1 Glutathione S-transferase theta 1 22q11.23
GULP1 GULP, engulfment adaptor PTB
domain containing 1 2q32.3-q33rs2004888
GWA
10q2613 rs17101921
GWA
11p141 rs1602565
GWA
16p1312 rs71992086
GWA_10q2
6.13 rs17101921
GWA_11p1
4.1
rs1602565
GWA_16p1
3.12 rs7192086
HINT1 Histidine triad nucleotide
binding protein 1 5q31.2
HLA-A Major histocompatibility
complex, class I, A 6p21.3
HLA-B Major histocompatibility
complex, class I, B 6p21.3
HLA-C Major histocompatibility
complex, class I, C 6p21.3

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 57
Continued
HLA-DQA1 Major histocompatibility
complex, class II, DQ alpha 1 6p21.3
Asthma; Celiac disease; Diabetes (type 1); Gluten-sensitive
enteropathy; HLA-DQA1 differential expression; Lung
adenocarcinoma; Metamizol-related agranulocytosis; Oligoarticular
juvenile idiopathic arthritis; Rheumatoid arthritis; Susceptibility to
onchocerciasis; Toxoplasmic encephalitis; Ximelagratan sensitivity
HLA-DQB Major histocompatibility
complex, class II, DQ beta 1 6p21.3
HLA-DRB1 Major histocompatibility
complex, class II, DR beta 1 6p21.3
HLA-E Major histocompatibility
complex, class I, 6p21.3 Bipolar disorder
HIST1H2BJ Histone cluster 1, H2bj 6p22.1 rs6913660
HOMER Homer homolog 2 (Drosophila) 15q24.3 rs17158184;
rs2306428
HP Haptoglobin 16q22.1 Hp1/2
Anemia; Atherosclerosis; Autoimmune diseases; Breast neoplasms;
Cardiovascular disease; Chronic hepatitis B; Chronic hepatitis C;
Coronary atherosclerosis; Crohn’s disease; Diabetic vascular disease;
Dyslipidemias; Diabetes mellitus (type 1); Diabetes mellitus (type 2);
Diabetic angiopathy; Diabetic nephropathy; Female genital
neoplasms; Hemochromatosis; Hepatitis B; HIV infections;
Hypersensitivity; Hypertension; Leukemia; Malaria; Myocardial
infarction; Nasopharingeal carcinoma; Parkinson’s disease;
Pasteurellaceae infections; Pregnancy-induced hypertension;
Primary sclerosis cholangitis; Retinal detachment; Sickle cell
anemia; Tuberculosis; Trachoma
HRH1 Histamine receptor H1 3p25
Allergy; Allergic contact dermatitis; Angioedema; Asthma; Atopic
dermatitis; Bronchial hyperreactivity; Hypersensitivity;
Inflammation; Learning disorders; Long QT syndrome; Memory
disorders; Mental disorders; Perennial allergic rhinitis; Pruritus;
Pulmonary eosinophilia; Respiratory hypersensitivity; Respiratory
tract diseases; Rhinitis; Urticaria; Sinusitis; Skin disorders; Sneezing;
Seasonal allergic rhinitis; Seizures
HSPA1B Heat shock 70kDa protein 1B 6q21.3 rs539689
HTR1A 5-Hydroxytryptamine
(serotonin) receptor 1A 5q11.2-q13
Alzheimer disease; Antidepressant sensitivity; Anxiety disorders;
Depression; Macular degeneration; Major depression; Mental
disorders; Neuroleptic-related weight gain in schizophrenia; Panic
disorder; Personality disorders; Psychotic disorders;
Schizophrenia-related weight gain; Sudden infant death
HTR2A 5-Hydroxytryptamine
(serotonin) receptor 2A 13q14-q21
rs6313;
rs6314;
rs6311
Alcohol dependence; Alzheimer disease; Anorexia nervosa;
Antidepressant-related response; Antipsychotic-related response;
Asperger’s syndrome; Attention-deficit hyperactivity disorder;
Autistic disorder; Bipolar disorder; Clozapine-induced weight gain;
Depression; Depressive disorder; Major depression; Major depressive
disorder; Memory performance; Mental disorders; Mental
retardation; Migraine; Mood disorders; Neuroleptic-induced weight
gain; Neuroleptic-related response; Neurotoxicity syndromes;
Obsessive-compulsive disorder; Personality disorders; Pervasive
child development disorders; Psychotic disorders; Substance abuse;
Response to citalopram therapy in major depressive disorder; Tardive
dyskinesia
HTR3A 5-Hydroxytryptamine
(serotonin) receptor 3A 11q23.1
HTR4 5-Hydroxytryptamine
(serotonin) receptor 4 5q31-q33
IDE Insulin-degrading enzyme 10q23-q25

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 58
Continued
IFNG Interferon, gamma 12q14 rs62559044
AIDS; Allergic contact dermatitis; Aortic aneurysm; Aplastic
anemia; Appendicitis; Asthma; Atherosclerosis; Autistic disorder;
Crohn’s disease; Drug-induced liver injury; Entamebiasis; Hepatitis;
Hepatitis C; Hepatocellular carcinoma; Hepatomegaly;
Inflammation; Job’s syndrome; Kidney angiomyolipoma; Kidney
failure; Myocardial infarction; Liver neoplasms; Lupus nephritis;
Multiple sclerosis; Liver cirrhosis; Liver diseases; Oral submucous
fibrosis; Renal cell carcinoma; Tuberculosis; Tuberous sclerosis;
Susceptibility to human immunodeficiency virus type 1
IGHA1 Immunoglobulin heavy constant
alpha 1 14q32.33
IL1A Interleukin 1, alpha 2q14
IL1B Interleukin 1, beta 2q14 rs1143634
rs16944
Alzheimer disease; Ankylosing spondylitis; Arsenic poisoning;
Body fat mass; Breast neoplasms; Bronchopulmonary dysplasia;
Colon cancer; Colonic neoplasms; Diabetic nephropathy; Distal
interphalangeal joint osteoarthritis; Entamebiasis; Experimental liver
cirrhosis; Fever; Gastric cancer; Gastric cancer and
Helicobacter pylori; Glioblastoma; IgA nephropathy; Inflammation;
Inflammatory bowel disease; Lung diseases; Major depression;
Major depressive disorder; Osteoporosis; Microvascular
complications of diabetes; Multiple sclerosis; Nervous system
diseases; Non-small cell lung cancer; Parkinson’s disease;
Postmenopausal osteoporosis; Primary open-angle glaucoma;
Pulmonary fibrosis; Skin diseases; Stomach neoplasms; Ulcerative
colitis
IL1RN Interleukin 1 receptor antagonist 2q14.2
Arsenic poisoning; Autistic disorder; Colonic neoplams; Chagas’
disease; Diabetes; Gastric cancer susceptibility after H. pylori
infection; Generalized aggressive periodontitis; Inflammatory bowel
disease; Interleukin 1 receptor antagonist deficiency; Memory
disorders; Metabolic syndrome; Multiple sclerosis; Osteoarthritis;
Osteoporosis; Prostatic neoplasms; Skin diseases; Stroke;
Susceptibility to microvascular complications of diabetes 4;
Tourette’s syndrome; Ulcer
IL3 Interleukin 3 (colony-stimulating factor,
multiple)
5q31.1
IL3RA Interleukin 3 receptor, alpha
(low affinity)
Xp22.3 or
Yp11.3
rs6603272
IL4 Interleukin 4 5q31.1
Allergic contact dermatitis; Arthritis; Asthma; Atopic dermatitis;
Autistic disorder; Autoimmune hypothyroidism; Bladder cancer;
Chronic periodontitis; Common variable immunodeficiency; Graves’
disease; Glioblastoma; Hypersensitivity; Psoriasis; Subacute
sclerosing panencephalitis; Systemic lupus erythematosus;
Thromboembolic stroke
IL10 Interleukin 10 1q31-q32 rs1800896;
rs1800872
Acquired immunodeficiency syndrome; Alcoholic liver disease;
Alzheimer disease; Appendicitis; Autistic disorder; Colitis;
Coronary heart disease; Crohn’s disease; Diabetes mellitus (type 1);
Enterocolitis; Entamebiasis; Experimental mammary neoplasms;
Graft vs host disease (acute); Hepatitis B; Hepatocellular carcinoma;
HIV infections; Inflammatory bowel disease; Irritable bowel
syndrome; Kawasaki disease; Leprosy; Lung neoplasms; Malaria;
Prostate cancer; Prostatic neoplasms; Psoriasis; Rheumatoid arthritis;
Severe malaria anemia; Skin carcinomas; Skin neoplasms; Squamous
cell carcinoma; Sudden infant death syndrome; Systemic lupus
erythematosus; Trachoma; Ulcerative colitis
IL12B
Interleukin 12B (natural killer
cell stimulatory factor 2,
cytotoxic lymphocyte
maturation factor 2, p40)
5q31.1-q33.1
Asthma; Atopic dermatitis; Bacillus Calmette-Guérin and Salmonella
infection; Colorectal cancer; Crohn’s disease; Diabetes mellitus (type
1); Familial atypical mycobacteriosis; Gastric cancer; Hypothermia;
Leprosy; Malaria; Psoriasis; Psoriasis vulgaris; Psoriatic arthritis;
Salmonella infection; Tuberculosis; Ulcerative colitis
IL18 Interleukin 18
(interferon-gamma-inducing
factor)
11q22.2-q22.3

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 59
Continued
IL18R1 Interleukin 18 receptor 1 2q12
IL18RAP Interleukin 18 receptor
accessory protein 2q12
IPO5 Importin 5 13q32.2
ITIH3/4 Inter-alpha (globulin) inhibitor,
H3/4 polypeptides 3p21.1
JARID2 Jumonji, AT rich interactive
domain 2 6p24-p23 rs9654600; rs2235258
KCNH2 Potassium voltage-gated channel, subfamily H
(eag-related), member 2
7q36.1
Arrhythmia; Bradycardia-induced long QT syndrome;
Drug-associated torsades de pointes; Long QT syndrome; Long QT
syndrome 1/2; Long QT syndrome 2; Long QT syndrome 2/3; Long
QT syndrome 2/5; Long QT syndrome 2/9; Nonfamiliar atrial
fibrillation (AF); Schizophrenia; Short QT syndrome 1; Torsades de
pointes
LEPR Leptin receptor 1p31
Acute lymphoblastic leukemia; Diabetes; Diabetes mellitus (type 2);
Glucocorticoid-induced hypertension; Hypogonadism; Impaired
glucose tolerance; Low bone mineral content; Morbid obesity;
Obesity; Osteoporosis; Risk of metabolic syndrome, diabetes or
vascular disease
LGR4 Leucine-rich repeat containing G
protein-coupled receptor 4 11p14-p13
LTA Lymphotoxin alpha (TNF
superfamily, member 1) 6p21.3
Susceptibility to leprosy 4; Susceptibility to myocardial infarction;
Susceptibility to psoriatic arthritis
MAGI1 Membrane associated guanylate
kinase, WW and PDZ domain
containing 1
3p14.1
MAGI2 Membrane associated guanylate
kinase, WW and PDZ domain
containing 2
7q21
MAGI3 Membrane associated guanylate
kinase, WW and PDZ domain
containing 3
1p12-p11.2
MBP Myelin basic protein 18q23
MC5R Melanocortin 5 receptor 18p11.2
MCHR1 Melanin-concentrating hormone
receptor 1 22q13.2
MCHR2 Melanin-concentrating hormone
receptor 2 6q16
MCTP2 Multiple C2 domains,
transmembrane 2 15q26.2
MDGA1
MAM domain containing
glycosylphosphatidylinositol
anchor 1
6p21 rs11759115
ME2
Malic enzyme 2,
NAD(+)-dependent,
mitochondrial
18q21
MED12 Mediator complex subunit 12 Xq13 FG syndrome 1; Lujan-Fryns syndrome; Opitz-Kaveggia syndrome
MEGF10 Multiple EGF-like-domains 10 5q33
MICB MHC class I polypeptide-related
sequence B 6p21.3
MLC1
Megalencephalic
leukoencephalopathy with
subcortical cysts 1
22q13.33 Megalencephalic leukoencephalopathy with subcortical cysts

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 60
Continued
MMP3 Matrix metallopeptidase 3
(stromelysin 1, progelatinase) 11q22.3
Abdominal aortic aneurysm; Breast neoplasms; Coronary
arteriosclerosis; Coronary disease; Coronary heart disease;
Rheumatoid arthritis; Schizophrenia
MMP9
Matrix metallopeptidase 9
(gelatinase B, 92 kDa gelatinase,
92 kDa type IV collagenase)
20q11.2-q13.1
MOG Myelin oligodendrocyte
glycoprotein
6p22.1
MTHFR Methylenetetrahydrofolate
reductase (NAD(P)H) 1p36.3 rs1801131; rs1801133
Abnormal spermatogenesis; Acute lymphocytic leukemia (ALL);
Alzheimer disease; Autistic disorder; B-cell chronic lymphocytic
leukemia; Bipolar disorder; Breast neoplasms; Budd-Chiari
syndrome; Cancer; Cardiovascular diseases; Cervical intraepithelial
neoplasia; Cleft lip; Cleft lip/palate; Clubfoot; Cognition disorders;
Colonic neoplasms; Colorectal neoplasms; Congenital cardiac
disease; Congenital heart defects; Coronary artery disease; Coronary
heart disease; Coronary restenosis; Decreased viability among
fetuses; Depression; Depressive disorder; Diabetic angiopathy;
Down’s syndrome; Endometrial neoplasms; Female infertility;
Folate-sensitive neural tube defects; Follicular lymphoma; Gastric
cancer; Glaucoma; Graft vs host disease; Homocystinuria;
Homocystinuria due to deficiency of
N(5,10)-methylenetetrahydrofolate reductase activity;
Hyperhomocysteinemia; Hypersensitivity; Hypertension; Ischemic
stroke; Liver diseases; Lower toxicity in 5-FU treatment; Lung
neoplasms; Lymphoma; Major depressive disorder; Male infertility;
Malnutrition; Maxillofacial abnormalities; Meningomyelocele;
Metabolic diseases; Microsatellite instability; Microvascular angina;
Migraine; Migraine with aura; MTHFR deficiency; Mucositis;
Neoplasm metastasis; Neural tube defects; Nitrous oxide sensitivity
in MTHFR deficiency; Non-Hodgkin lymphoma; Orofacial cleft 1;
Precursor cell lymphoblastic leukemia-lymphoma; Pre-eclampsia;
Primary open-angle glaucoma; Prostatic neoplasms; Retinal artery
occlusion; Rheumatoid arthritis; Smallpox vaccine; Spinal cord
diseases; Stomach neoplasms; Stroke; Sudden hearing loss;
Thrombophilia; Thrombosis; Uterine cervical neoplasms
MUTED Muted homolog (mouse) 6p25.1-p24.3
NALCN Sodium leak channel,
nonselective 13q33.1 rs2152324
NCAM1 Neural cell adhesion molecule 1 11q23.1
NDEL1 NudE nuclear distribution gene
E homolog (A. nidulans)-like 1 17p13.1 rs17806986
NEFM Neurofilament, medium
polypeptide 8p21
NEUROG1 Neurogenin 1 5q23-q31
NOS1 Nitric oxide synthase 1
(neuronal)
12q24.2-q24.3
1 Susceptibility to infantile hypertrophic pyloric stenosis 1
NOS1AP Nitric oxide synthase 1
(neuronal) adaptor protein 1q23.3 rs12742393
NOTCH4 Notch 4 6p21.3 rs3131296 HIV-1 in humans
NPHP1 Nephronophthisis 1 (juvenile) 2q13
Joubert syndrome 4; Juvenile nephronophthisis 1; Juvenile nephronophthisis; Senior-Loken syndrome-1
NPY Neuropeptide Y 7p15.1
Alcoholism; Anorexia nervosa; Anxiety disorders; Anxious
depression; Appetite disorders; Birth weight; Cachexia; Carotid
atherosclerosis; Cerebral infarction; Diabetes mellitus (type 2);
Essential hypertension; Hypercholesterolemia; Hyperlipidemias;
Hypertriglyceridemia; Ischemic stroke; Left ventricular hypertrophy;
Myocardial infarction; Obesity; Stress
NQO2 NAD(P)H dehydrogenase,
quinone 2 6pter-q12 Breast cancer susceptibility

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 61
Continued
NR4A2 Nuclear receptor subfamily 4,
group A, member 2 2q22-q23 Parkinson’s disease
NRG1 Neuregulin 1 8p12
rs2439272;
rs35753505;
rs473376;
rs10503929;
rs7825588;
rs6994992;
rs4623364
NRG2 Neuregulin 2 5q23-q33
NRG3 Neuregulin 3 10q22-q23
rs7825588;
rs10883866;
rs10748842;
rs6584400
NRGN Neurogranin (protein kinase C
substrate, RC3) 11q24 rs12807809; rs7113041
NRXN1 Neurexin 1 2p16.3
NTF3 Neurotrophin 3 12p13
NTNG1 Netrin G1 1p13.3
NTRK3 Neurotrophic tyrosine kinase,
receptor, type 3 15q25 rs999905 rs4887348
NUMBL Numb homolog (Drosophila)-like 19q13.13-q13.
2
OLIG2 Oligodendrocyte lineage
transcription factor 2 21q22.11 rs762237; rs2834072
OPCML Opioid binding protein/cell
adhesion molecule-like 11q25 rs3016384Somatic epithelial ovarian cancer; Somatic ovarian cancer
OXSR1 Oxidative-stress responsive 1 3p22.2
PALB2 Partner and localizer of BRCA2 16p12.2
PCM1 Pericentriolar material 1 8p22-p21.3 Papillary thyroid carcinoma
PCNT Pericentrin 21q22.3
PDE4B Phosphodiesterase 4B,
cAMP-specific 1p31 rs910694; rs741271
PDE4D Phosphodiesterase 4D,
cAMP-specific 5q12 rs1120303
PDILM5 PDZ and LIM domain 5 4q22
PDE7B Phosphodiesterase 7B 6q23-q24 rs9389370
PGBD1 PiggyBac transposable element
derived 1 6p22.1 rs13211507
PICALM Phosphatidylinositol binding
clathrin assembly protein 11q14 rs3851179
PICK1 Protein interacting with PRKCA 1 22q13.1
PIK3C3 Phosphoinositide-3-kinase, class 3 18q12.3
PI4K2B Phosphatidylinositol 4-kinase type
2 beta 4p15.2
PLA2G4A Phospholipase A2, group IVA
(cytosolic, calcium-dependent) 1q25 rs10798059Deficiency of phospholipase A2, group IV A
PLAT Plasminogen activator, tissue 8p12 Familial hyperfibrinolysis, due to increased release of PLAT;
Plasminogen activator deficiency

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 62
Continued
PLXNA2 plexin A2 1q32.2
rs1327175;
rs841865
PPP1R1B Protein phosphatase 1, regulatory
(inhibitor) subunit 1B 17q12 rs907094
PPP3CC Protein phosphatase 3, catalytic
subunit, gamma isozyme 8p21.3 rs10108011
PRDX6 Peroxiredoxin 6 1q25.1
rs1295645;
rs11405;
rs6759;
rs1046240;
rs8383
PRODH Proline dehydrogenase (oxidase)
1 22q11.21
PRSS16 Protease, serine, 16 (thymus) 6p21 rs6932590
PSEN2 Presenilin 2 (Alzheimer disease 4) 1q31-q42 rs1295645
Alzheimer disease; Central nervous system diseases; Dilated
cardiomyopathy; Frontotemporal dementia; Ischemic stroke; Left
ventricular dysfunction; Left ventricular hypertrophy; Peripartum
cardiomyopathy; Schizophrenia
PTGS2
Prostaglandin-endoperoxide
synthase 2 (prostaglandin G/H
synthase and cyclooxygenase
1q25.2-q25.3 rs2745557
Acute pancreatitis; Adenocarcinoma; Adenoma; Adenomatous
polyposis coli; Amyotrophic lateral sclerosis; Cholangiocarcinoma;
Basal cell carcinoma; B-cell chronic lymphocytic leukemia; B-cell
lymphoma; Asthma; Breast neoplasms; Carcinoma; Carcinoma in
situ; Autistic disorder; Esophageal neoplasms; Coronary artery
disease; Diabetes mellitus (type 2); Drug-induced abnormalities;
Duodenal ulcer; Colonic neoplasms; Colorectal neoplasms;
Experimental liver cirrhosis; Glioma; Hepatocellular carcinoma;
Inflammation; Intestinal polyps; Ischemic stroke; Ischemic
proliferative retinopathy; Leiomyosarcoma; Kidney neoplasms;
Myocardial infarction; Myocardial ischemia; Non-small cell lung
carcinoma; Oral submucous fibrosis; Pancreatic neoplasms; Pituitary
neoplasms; Renal cell carcinoma; Prostatic neoplasms; Inflammation;
Intestinal polyps; Ischemic stroke; Ischemic proliferative retinopathy;
Leiomyosarcoma; Kidney neoplasms; Myocardial infarction;
Myocardial ischemia; Non-small cell lung carcinoma; Oral
submucous fibrosis; Pancreatic neoplasms; Pituitary neoplasms;
Renal cell carcinoma; Prostatic neoplasms; Skin diseases; Squamous
cell carcinoma; Stomach neoplasms; Stomach ulcer; Tongue
neoplasms; Urinary bladder neoplasms; Transitional cell carcinoma
PTPRZ1 Protein tyrosine phosphatase,
receptor-type, Z polypeptide 1 7q31.3 Susceptibility to H. pylori infection
QKI Quaking homolog, KH domain
RNA binding (mouse) 6q26
RNABP1 RAN binding protein 1 22q11.21 rs2238798;
rs175162
RAPGEF6 Rap guanine nucleotide exchange
factor (GEF) 6 5q31.1
RELN Reelin 7q22 rs7341475Lissencephaly syndrome, Norman-Roberts type
RGS4 Regulator of G-protein signaling 4 1q23.3 rs2661319
(SNP16)
RPGRIP1L RPGRIP1-like 16q12.2 rs9922369COACH syndrome; Joubert syndrome 7; Meckel syndrome, type 5
RPP21 Ribonuclease P/MRP 21kDa
subunit 6p22.1 rs3130375
RTN4 Reticulon
4 2p16.3
RTN4R Reticulon 4 receptor 22q11.21
SAT1 Spermidine/spermine
N1-acetyltransferase 1 Xp22.1

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 63
Continued
SCNB Synuclein, beta 5q35 Lewy body dementia
SCZD1 Schizophrenia disorder 1 5q11.2-q13.3
SCZD2 Schizophrenia disorder 2 11q14-q21
SCZD3 Schizophrenia disorder 3 6p24-p22
SCZD6 Schizophrenia disorder 6 8p21
SCZD7 Schizophrenia disorder 7 13q32
SCZD8 Schizophrenia disorder 8 18p
SCZD10 Schizophrenia disorder 10 15q15
SCZD11 Schizophrenia susceptibility
locus, chromosome 10q-related 10q22.3
SCZD12 Schizophrenia 12 1p
SDCCAG8 CCCAP SLSN7
Serologically defined colon
cancer antigen 8
1q43
SELENBP1 Selenium binding protein 1 1q21.3
SFRP1 Secreted frizzled-related protein 1 8p11.21
SH2B1 SH2B adaptor protein 1 16p11.2
SHANK3 SH3 and multiple ankyrin repeat
domains 3 22q13.3
Chromosome 22q13.3 deletion syndrome-related autism;
Chromosome 22q13.3 deletion syndrome
SHMT1 Serine hydroxymethyltransferase
1 (soluble) 17p11.2
SIGMAR1 Sigma non-opioid intracellular
receptor 1 9p13.3
SLC1A1
Solute carrier family 1
(neuronal/epithelial high affinity
glutamate transporter, system
Xag), member 1
9p24
SLC1A2
Solute carrier family 1 (glial high
affinity glutamate transporter),
member 2
11p13-p12
SLC1A3
Solute carrier family 1 (glial high
affinity glutamate transporter),
member 3
5p13
SLC1A6
Solute carrier family 1 (high
affinity aspartate/glutamate
transporter), member 6
19p13.12
SLC6A1
Solute carrier family 6
(neurotransmitter transporter,
GABA), member 1
3p25-p24
SLC6A3
Solute carrier family 6
(neurotransmitter transporter,
dopamine), member 3
5p15.3 rs6347
Anxiety disorders; Attention-deficit hyperactivity disorder; Bipolar
affective disorder; Bipolar disorder; Brain diseases; Cocaine
dependence; Cocaine-induced paranoia; Major depressive disorder;
Parkinson’s disease; Parkinsonian disorders; Pervasive development
disorders; Protection against nicotine dependence; Susceptibility to
tobacco addiction; Tic disorders; Tourette’s syndrome

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 64
Continued
SLC6A4
Solute carrier family 6
(neurotransmitter transporter,
serotonin), member 4
17q11.2
Alcoholism; Alzheimer disease; Anorexia nervosa; Anxiety
disorders; Anxiety-related personality traits; Attention-deficit
hyperactivity disorder; Autistic disorder; Bipolar affective disorder
and personality traits; Bipolar affective disorders; Bipolar disorder;
Brain diseases; Chronobiology disorders; Diabetes mellitus type 2;
Frontotemporal lobar degeneration; Irritable bowel syndrome; Major
depressive disorder; Migraine with aura; Mood disorders;
Obsessive-compulsive disorder; Pain threshold; Primary insomnia;
Pulmonary hypertension; Seasonal affective disorder; Sleep
disorders; Susceptibility to major depression, to attention-deficit
hyperactivity disorder, to autism and rigid-compulsive behaviors;
Susceptibility to obsessive-compulsive disorder; Sudden infant death;
Tinnitus
SLC6A9
Solute carrier family 6
(neurotransmitter transporter,
glycine), member 9
1p33
SLC12A2
Solute carrier family 12
(sodium/potassium/chloride
transporters), member 2
5q23.3
SLC12A5
Solute carrier family 12
(potassium/chloride transporter),
member 5
20q13.12
SLC17A7
Solute carrier family 17
(sodium-dependent inorganic
phosphate cotransporter), member 7
19q13
SLC18A1 Solute carrier family 18 (vesicular
monoamine), member 1 8p21.3 rs2270641
SMARCA2
SWI/SNF related, matrix
associated, actin dependent
regulator of chromatin, subfamily a,
member 2
9p22.3
rs2296212;
rs3793490;
rs3763627
SNAP25 Synaptosomal-associated protein,
25 kDa 20p12-p11.2
SNAP29 Synaptosomal-associated protein,
29 kDa 22q11.21
Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar
keratoderma syndrome
SOX10 SRY (sex determining region
Y)-box 10 22q13.1 rs139887
PCWH; PCWH syndrome; Waardenburg syndrome, type 2E, with or
without neurologic involvement; Waardenburg syndrome, type 4C;
Waardenburg syndrome, type IIE; Waardenburg-Shah syndrome;
Yemenite deaf-blind hypopigmentation syndrome
SP4 Sp4 transcription factor 7p15.3
rs12673091;
rs12668354;
rs12673091;
rs3735440;
rs11974306;
rs1018954
SRR Serine racemase 17p13 rs408067
ST8SIA2 ST8 alpha-N-acetyl-neuraminide
alpha-2,8-sialyltransferase 2 15q26 rs4586379; rs2168351
STX1A Syntaxin 1A (brain) 7q11.23
STX7 Syntaxin 7 6q23.1
SYNGAP1 Synaptic Ras GTPase activating
protein 1 6p21.3 Autosomal dominant mental retardation 5
SULT4A1 Sulfotransferase family 4A,
member1 22q13.2
SYN2 Synapsin II 3p25

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 65
Continued
SYN3 Synapsin III 22q12.3
SYNGR1 Synaptogyrin 1 22q13.1 rs715505
SYT11 Synaptotagmin XI 1q21.2
TAAR6 Trace amine associated receptor 6 6q23.2
TAP1
Transporter 1, ATP-binding
cassette, sub-family B
(MDR/TAP)
6p21.3
Allergic rhinitis; Bare lymphocyte syndrome (type I); Cervical
neoplasia; Dengue viral infection; Hypersensitivity pneumonitis
TARDBP TAR DNA binding protein 1p36.22
TBP TATA box binding protein 6q27 Huntington disease-like-4; Parkinson’s disease
TCF4 Transcription factor 4 18q21.1 rs9960767Pitt-Hopkins syndrome; Risk of bipolar disorder
TDO2 Tryptophan 2,3-dioxygenase 4q31-q32
TH Tyrosine hydroxylase 11p15.5 rs6356 Segawa syndrome, recessive
TNF Tumor necrosis factor 6p21.3 rs1800629
Acute kidney failure; Alzheimer disease; Anemia; Arsenic
poisoning; Asthma; Behçet’s disease; Bipolar affective disorder;
Breast neoplasms; Bronchiectasis; Cerebral malaria; Chronic
allograft nephropathy; Coronary artery disease; Coronary restenosis;
Diaphragmatic hernia; Experimental diabetes mellitus; Experimental
liver cirrhosis; Fever; Hemochromatosis; Hyperalgesia;
Hypersensitivity; Hypothermia; Infection; Inflammation; Irritable
bowel syndrome; Listeria infections; Lung diseases; Lung
neoplasms; Major depressive disorder; Malaria; Microchimerism and
diminished immune responsiveness; Migraine; Multiple organ
failure; Oral submucous fibrosis; Pain; Plasmodium falciparum blood
infection; Postmenopausal osteoporosis; Psoriasis; Pulmonary
fibrosis; Pulmonary tuberculosis; Reperfusion injury; Respiratory
hypersensitivity; Respiratory tract diseases; Rheumatic heart disease;
Rheumatoid arthritis; Sepsis; Septic shock; Skin diseases; Stomach
neoplasms; Stomach ulcer; Systemic lupus erythematosus; Ulcerative
colitis; Vascular dementia
TP53 Tumor protein p53 17p13.1 rs1042522
Adrenal cortical carcinoma; Alzheimer disease; Bladder neoplasms;
Breast neoplasms; Cervical intraepithelial neoplasia; Choroid plexus
papilloma; Colonic neoplasms; Colorectal neoplasms; Esophageal
cancer; Gastric cancer; Glioblastoma; Head and neck neoplasms;
Hepatocellular carcinoma; Histiocytoma; Li-Fraumeni syndrome 1;
Lung neoplasms; Lymphocytic leukemia; Multiple malignancy
syndrome; Nasopharyngeal carcinoma; Neoplasms; Osteosarcoma;
Ovarian neoplasms; Pancreatic cancer; Pancreatic carcinoma;
Pancreatic neoplasms; Prostatic neoplasms; Rhabdomyosarcoma;
Rheumatoid arthritis; Skin neoplasms; Telangiectasia; Thyroid
carcinoma
TPH1 Tryptophan hydroxylase 1 11p15.3-p14rs1800532
Bulimia; Cardiovascular diseases; Major depression;
Obsessive-compulsive disorder; Pulmonary hypertension; Risk for
suicidal behavior; Slower response to fluvoxamine
TRIM32 Tripartite motif containing 32 9q33.1
TSNAX Translin-associated factor X 1q42.1
UFD1L Ubiquitin fusion degradation 1
like (yeast) 22q11.21
VEGFA Vascular endothelial
growth factor A 6p12
Acute myocardial infarction; Alzheimer disease; Asthma;
Atherosclerosis; Biliary atresia; Bladder cancer; Bladder neoplasms;
Colon cancer; Colonic neoplasms; Diabetes mellitus (type 2);
Diabetic nephropathy; Diabetic retinopathy; Endometriosis;
Esophageal cancer; Experimental liver cirrhosis; Gastric cancer;
Glioblastoma; Liver neoplasms; Macular degeneration; Neoplasms;
Non-small cell lung carcinoma; Ovarian cancer; Psoriasis;
Retinopathy; Rhabdomyosarcoma; Rheumatoid arthritis;
Squamous cell carcinoma

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 66
Continued
VIPR2 Vasoactive intestinal peptide receptor 2 7q36.3
WNK3 WNK lysine deficient protein kinase 3 Xp11.22
XBP1 X-box binding protein 1 22q12 Susceptibility to bipolar disorder; Susceptibility to major affective
disorder-7
XRCC1 X-ray repair complementing defective
repair In Chinese hamster cells 4 19q13.2 rs6452536 rs35260
Acute lymphoblastic leukemia; Bladder neoplasms; Breast cancer;
Breast neoplasms; Gastric cancer; Mesothelioma; Non-small cell
lung cancer; Occupational diseases; Prostatic neoplasms; Squamous
cell carcinoma of the head and neck
XRCC4 X-ray repair complementing defective
repair in Chinese hamster cells 4 5q14.2
YWHAE
Tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein,
epsilon polypeptide
17p13.3
YWHAH
Tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein,
eta polypeptide
22q12.3
ZBED4 Zinc finger, BED-type containing 4 22q13.33
ZDHHC8 Zinc finger, DHHC-type containing 8 22q11.21
ZNF804A ZInc finger protein 804A 2q32.1
rs1344706;
rs7597593;
rs1344706;
rs4667000;
rs1366842;
rs3731834
(Updated from Cacabelos and Martínez-Bouza [17], and Cacabelos et al. [1]).
Table 2. Pharmacogenomics of Neuroleptics.
Drug Features
Aripiprazole
Category: Atypical antipsychotic; Arilpiperazine
Mechanism: Full agonist: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT6, 5-HT receptors; partial agonist: D2 and 5-HT1A receptors;
antagonist: 5-HT2A receptor
Genes: ABCB1, ADRA1A, CYP2D6, CYP3A4, DRD2, DRD3, HRH1, HTR1A, HTR1B, HTR1D, HTR2A, HTR2C, HTR7
Substrate: CYP2D6 (major), CYP3A4 (major)
Benperidol Category: Antipsychotic, Neuroleptic; Butyrophenone
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors
Genes: DRD1, DRD2
Bromperidol
Category: Antipsychotic, Neuroleptic; Butyrophenone
Mechanism: D2 receptor antagonist; moderate serotonin 5-HT2 receptor antagonist
Genes: ABCB1, ADRA1A, CYP2D6, DRD2, HTR2A
Substrate: CYP2D6 (minor), CYP3A4 (major), UGTs
Inhibitor: CYP2D6 (moderate)
Chlorpromazine
Category: Phenothiazine antipsychotic; Aliphatic phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; has a strong anticholinergic effect;
weakly blocks ganglionic, antihistaminic and antiserotonergic receptors; blocks α-adrenergic receptors (strong); inverse
agonist: 5-HT6, 5-HT7; antagonist: 5-HT1A, 5-HT2c
Genes: ABCB1, ACACA, ADRA1A, ADRA2A, ADRA2B, ADRA2C, BDNF, CYP1A2, CYP2D6, CYP3A4, CYP2E1,
DAO, DRD1, DRD2, DRD3, FABP1, FMO1, HRH1, HTR1A, HTR1E, HTR2A, HTR2C, HTR6, HTR7, KCNE2, LEP,
NPY, SCN5A, UGT1A3, UGT1A4
Substrate: CYP1A2 (minor), CYP2D6 (major), CYP3A4 (minor), UGT1A3, UGT1A4
Inhibitor: CYP2D6 (strong), CYP2E1 (weak), DAO

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Continued
Clozapine
Category: Atypical antipsychotic; Dibenzodiazepine
Mechanism: Antagonist of histamine H1, cholinergic and α1-adrenergic receptors; antagonist: 5-HT1A, 5-HT2B; full agonist:
5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F; inverse agonist: 5-HT6, 5-HT7
Genes: ABCB1, ADRA1A, ADRA1B, ADRA1D, ADRB3, APOA5, APOC3, APOD, CNR1, CYP1A2, CYP2A6,
CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, DRD1, DRD2, DRD3, DRD4, DTNBP1, FABP1, GNAS1, GNB3,
GSK3B, HLAA, HRH1, HRH2, HRH4, HTR1A, HTR1B, HTR1D, HTR1E, HTR1F, HTR2A, HTR2B, HTR2C, HTR3A,
HTR6, HTR7, LPL, RGS2, SLC6A2, SLC6A4, TNF, UGT1A3, UGT1A4
Substrate: ABCB1, CYP1A2 (major), CYP2A6 (minor), CYP2C8/9 (minor), CYP2C19 (minor), CYP2D6 (minor),
CYP3A4 (major), FMO3, UGT1A3, UGT1A4
Inhibitor: CYP1A2 (weak), CYP2C8/9 (moderate), CYP2C19 (moderate), CYP2D6 (moderate), CYP2E1 (weak),
CYP3A4 (weak)
Droperidol
Category: Atypical antipsychotic; Butyrophenone
Mechanism: Blocks dopaminergic and α-adrenergic receptors
Genes: ABCC8, ADRA1A, ADRAB1, ADRA2A, DRD2, CHRM2, CYP2C9, CYP2C19, CYP3D6, CYP3A4, KCNE1,
KCNE2, KCNH2, KCNJ11, KCNQ1, SCN5A
Substrate: CYP2C9 (major), CYP2C19 (major), CYP2D6 (major), CYP3A4 (major)
Fluphenazine
Category: Typical antipsychotic; Piperazine phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; inverse agonist: 5-HT7; antagonist:
5-HT2A
Genes: ABCB1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, DRD1, DRD2, HRH1,
HTR2A, HTR7
Substrate: CYP2D6 (major)
Inhibitor: CYP1A2 (weak), CYP2C9 (weak), CYP2D6 (strong), CYP2E1 (weak)
Flupenthixol Category: Typical antipsychotic; Thioxanthene
Mechanism: Blocks postsynaptic dopaminergic receptors
Genes: DRD1, DRD2
Haloperidol
Category: Typical antipsychotic; Butyrophenone
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; antagonist: 5-HT2A, 5-HT2B
Genes: ABCB1, ABCC1, ADRA1A, ADRA2A, BDNF, CHRM2, CYP1A2, CYP2C9, CYP2D6, CYP3A4, DRD1, DRD2,
DRD4, DTNBP1, FOS, GRIN2B, GSK3B, GSTP1, HRH1, HTR2A, HTR2B, HTT, IL1RN, KCNE1, KCNE2, KCNH2,
KCNJ11, KCNQ1, SCN5A, UGTs
Substrate: CBR, CYP1A1 (minor), CYP1A2 (minor), CYP2C8/9 (minor), CYP2C19 (minor), CYP2D6 (major), CYP3A4
(major), UGTs
Inhibitor: CYP2D6 (moderate), CYP3A4 (moderate)
Loxapine
Category: Typical antipsychotic; Dibenzoxazepine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; blocks serotonin 5-HT2 receptors; inverse
agonist: 5-HT2c, 5-HT6
Genes: ADRA1A, DRD1, DRD2, HRH1, HTR2A, HTR2C, HTR6, KCNE2, SCN5A, UGT1A4
Substrate: UGT1A4
Mesoridazine
Category: Typical antipsychotic; Phenothiazine
Mechanism: Putative dopaminergic, cholinergic, and adrenergic inhibition
Genes: ADRA1A, DRD2, CHRM2, CYP2J2, KCNE1, KCNE2, KCNH2, KCNJ11, KCNQ1, SCN5A
Substrate: CYP2J2
Molindone
Category: Typical antipsychotic; Dihydroindolone
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; has a strong anticholinergic effect; weak
ganglionic, antihistaminic and antiserotonergic block; strong α-adrenergic block; antagonist: 5-HT2A
Genes: ADRA1A, CYPs, DRD2,DRD3, HRH1, HTR1A, HTR1E, HTR2A, HTR2C
Olanzapine
Category: Atypical antipsychotic; Thienobenzodiazepine
Mechanism: Strong antagonist of serotonin 5-HT2A and 5-HT2C, 5-HT7, dopaminergic D1-4, histamine H1 and α1-adrenergic
receptors; antagonist: 5-HT2A, 5-HT3 and muscarinic M1-5; full agonist: 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F; inverse agonist:
5-HT2c, 5-HT6
Genes: ABCB1, ADRA1A, ADRB3, APOA5, APOC3, CHRM1, CHRM2, CHRM3, CHRM4, CHRM5, COMT,
CYP1A2, CYP2C8/9, CYP2C19, CYP2D6, CYP3A4, DRD1, DRD2, DRD3, DRD4, FMO1, GNB3, GRM3, HRH1,
HRH2, HTR1A, HTR1B, HTR1D, HTR1E, HTR1F, HTR2A, HTR2C, HTR3A, HTR6, HTR7, KCNH2, LEP, LEPR,
LPL, RGS2, SLC6A2, TNF, UGT1A4
Substrate: CYP1A2 (major), CYP2D6 (major), UGT1A4
Inhibitor: CYP1A2 (weak), CYP2C8/9 (weak), CYP2C19 (weak), CYP2D6 (weak), CYP3A4 (weak)

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Continued
Paliperidone
Category: Atypical antipsychotic; Benzisoxazole
Mechanism: Serotonin and dopamine receptor antagonist; has high affinity for α1, D2, H1, and 5-HT2C receptors; low
affinity for muscarinic and 5-HT1A receptors
Genes: ABCB1, ADRA1A, ADRA1B, ADRA1D, CHRMs, CYP2D6, CYP3A4, DRD2, HRH1, HTR1A, HTR2A, UGTs
Substrate: ABCB1, ADH, CYP2D6 (major), CYP3A4 (major), UGTs
Inhibitor: ABCB1, CYP2D6 (moderate), CYP3A4 (moderate)
Periciazine
Category: Typical antipsychotic; Piperidine phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; blocks α-adrenergic receptors; inverse
agonist: 5-HT6, 5-HT7; antagonist: 5-HT2A, 5-HT2c
Genes: ADRA1A, CYP2D6, CYP3A4/5, DRD1, DRD2, DRD3, HTR2A, HTR2C, HTR6, HTR7
Substrate: CYP2D6, CYP3A4
Perphenazine
Category: Typical antipsychotic; Piperazine phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors
Genes: ABCB1, CYP1A2, CYP2C8/9, CYP2C19, CYP2D6, CYP3A4, DRD1, DRD2, RGS4
Substrate: CYP1A2 (major), CYP2C8/9 (major), CYP2C18/19 (major), CYP2D6 (major), CYP3A4/5 (major)
Inhibitor: CYP1A2 (weak), CYP2D6 (weak)
Pimozide
Category: Typical antipsychotic; Difenylbutylpiperidine
Mechanism: Dopaminergic antagonist; antagonist: 5-HT1A, 5-HT2A,5-HT7
Genes: ABCB1, ADRA1A, CHRM2, CYP1A2, CYP2C19, CYP2D6, CYP2E1, CYP3A4, DRD2, HRH1, HTR1A,
HTR2A, HTR7, KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A
Substrate: CYP1A2 (minor), CYP3A4 (major)
Inhibitor: CYP2C19 (weak), CYP2D6 (strong), CYP2E1 (weak), CYP3A4 (moderate)
Pipotiazine
Category: Typical antipsychotic; Piperidine phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors
Genes: CYP2D6, CYP3A4, DRDs
Substrate: CYP2D6, CYP3A4
Prochlorperazine
Category: Typical antipsychotic; Piperazine phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors; strong α-adrenergic and anticholinergic
block
Genes: ABCB1, ADRA1A, CYPs, DRD1, DRD2
Quetiapine
Category: Atypical antipsychotic; Dibenzothiazepine
Mechanism: Serotonergic (5-HT1A, 5-HT2A, 5-HT2), dopaminergic (D1 and D2), histaminergic H1, and adrenergic (α1- and
α2-) receptor antagonist; full agonist: 5-HT1A, 5-HT1D, 5-HT1F, 5-HT2A
Genes: ABCB1, ADRA1A, ADRA2A, CYP3A4, CYP2D6, DRD1, DRD2, DRD4, HRH1, HTR1A, HTR1D, HTR1E,
HTR1F, HTR2A, HTR2B, KCNE1, KCNE2, KCNH2, KCNQ1, RGS4, SCN5A
Substrate: CYP3A4 (major), CYP2D6 (minor)
Risperidone
Category: Atypical antipsychotic; Benzisoxazole
Mechanism: Serotonergic, dopaminergic, α1-, α2-adrenergic and histaminergic receptor antagonist; low-moderate affinity
for 5-HT1C, 5-HT1D, and 5-HT1A receptors, low affinity for D1; inverse agonist: 5-HT2c, 5-HT6, 5-HT7
Genes: ABCB1, ADRA1A, ADRA1B, ADRA1D, APOA5, COMT, CYP2D6, CYP2A4, CYP3A4, DRD1, DRD2, DRD3,
DRD4, FOS, GRM3, HRH1, HTR1A, HTR1B, HTR1C, HTR1D, HTR1E, HTR1F, HTR2A, HTR2C, HTR3A, HTR6,
HTR7, KCNE2, KCNH2, PON1, RGS2, RGS4, SCN5A, SLC6A2, SLC6A4
Substrate: ABCB1, CYP2D6 (major), CYP3A4 (minor)
Inhibitor: ABCB1, CYP2D6 (weak), CYP3A4 (weak)
Sulpiride
Category: Atypical antipsychotic; Benzamide
Mechanism: Postsynaptic D2 antagonist
Genes: CYP2D6, CYP3A4, DRD2
Substrate: CYP2D6
Thioridazine
Category: Typical antipsychotic; Phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors; blocks α-adrenergic receptors (strong); inverse
agonist: 5-HT6, 5-HT7; antagonist: 5-HT2c
Genes: ABCB1, ADRA1A, CHRM2, CYP1A2, CYP2C8/9, CYP2D6, CYP2C19, CYP2E1, CYP2J2, DRD2, FABP1,
HRH1, HTR6, HTR7, HTR2C, KCNE1, KCNE2, KCNH2, KCNJ11, KCNQ1, SCN5A
Substrate: CYP1A2 (major), CYP2C19 (minor), CYP2D6 (major), CYP2J2 (major), CYP3A4 (major)
Inhibitor: ADRA1, ADRA2, ADRBs, CYP1A2 (weak), CYP2C8/9 (weak), CYP2D6 (moderate), CYP2E1 (weak), DRD1
Thiothixene
Category: Typical antipsychotic; Thioxanthene
Mechanism: Inhibits dopamine receptors; blocks α-adrenergic receptors; antagonist: 5-HT2a
Genes: ADRA1A, CYP1A2, CYP2D6, DRD2, HRH1, HTR2A, KCNE1, KCNE2, KCNQ1, KCNH6, SCN5A
Substrate: CYP1A2 (major)
Inhibitor: CYP2D6 (weak)

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 69
Continued
Trifluoperazine
Category: Typical antipsychotic; Phenothiazine
Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors; blocks α-adrenergic receptors
Genes: ABCB1, ADRA1A, CYP1A2, DRD2, IL12B, UGT1A4
Substrate: CYP1A2 (major), UGT1A4
Ziprasidone
Category: Atypical antipsychotic; Benzylisothiazolylpiperazine
Mechanism: High affinity for: D2, D3, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT1D and α1-adrenergic receptors; moderate affinity for
histamine H1 receptors; antagonist: D2, 5-HT1A, 5-HT2A, and 5-HT1D; full agonist: 5-HT1B, 5-HT1D; partial agonist: 5-HT1A;
inverse agonist: 5-HT2c, 5-HT7
Genes: ADRA1A, AOX1, CYP1A2, CYP2D6, CYP3A4, DRD2, DRD3, DRD4, HRH1, HTR1A, HTR1B, HTR1D,
HTR1E, HTR2A, HTR2C, HTR7, KCNE2, KCNH2, RGS4, SCN5A
Substrate: AOXs, CYP1A2 (minor), CYP3A4 (major), HTR1A
Inhibitor: CYP2D6 (moderate), CYP3A4 (moderate), HTR2A, DRD2
Zuclopenthixol
Category: Typical antipsychotic; Thioxanthene
Mechanism: Blocks postsynaptic mesolimbic dopaminergic receptors
Genes: CYP2D6, DRD1, DRD2
Substrate: CYP2D6 (major)
Symbols: ABCB1: ATP-binding cassette, sub-family B (MDR/TAP), member 1, ACACA: Acetyl-Coenzyme A carboxylase alpha, ADRA1A: Adrenergic, al-
pha-1A-, receptor, ADRA1B: Adrenergic, alpha-1B-, receptor, ADRB3: Adrenergic, beta-3-, receptor, ADRA1D: Adrenergic, alpha-1D-, receptor, AOX1: Al-
dehyde oxidase 1, APOA5: Apolipoprotein A-V, APOC3: Apolipoprotein C-III, APOD: Apolipoprotein D, BDNF: Brain-derived neurotrophic factor, CFTR:
Cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7), CHRMs: Muscarinic receptors, CHRM1: Cholinergic
receptor, muscarinic 1, CHRM2: Cholinergic receptor, muscarinic 2, CHRM3: Cholinergic receptor, muscarinic 3, CHRM4: Cholinergic receptor, muscarinic
4, CHRM5: Cholinergic receptor, muscarinic 5, CNR1: Cannabinoid receptor 1 (brain), COMT: Catechol-O-methyltransferase, CYP1A2: Cytochrome P450,
family 1, subfamily A, polypeptide 2, CYP2A6: Cytochrome P450, family 2, subfamily A, polypeptide 6, CYP2C19: Cytochrome P450, family 2, subfamily C,
polypeptide 19, CYP2C8: Cytochrome P450, family 2, subfamily C, polypeptide 8, CYP2C9: Cytochrome P450, family 2, subfamily C, polypeptide 9,
CYP2D6: Cytochrome P450, family 2, subfamily D, polypeptide 6, CYP2J2: Cytochrome P450, family 2, subfamily J, polypeptide 2, CYP2E1 : Cytochrome
P450, family 2, subfamily E, polypeptide 1, CYP3A4: Cytochrome P450, family 3, subfamily A, polypeptide 4, DRDs: Dopamine receptors, DRD1: Dopamine
receptor D1, DRD2: Dopamine receptor D2, DRD3: Dopamine receptor D3, DRD4: Dopamine receptor D4, DTNBP1: Dystrobrevin binding protein 1,
FABP1: Fatty acid binding protein 1, liver, FMO1: Flavin containing monooxygenase 1, FOS: FBJ murine osteosarcoma viral oncogene homolog, GNAS:
GNAS complex locus, GNB3: Guanine nucleotide binding protein (G protein), beta polypeptide 3, GRIN2B: Glutamate receptor, ionotropic, N-methyl
D-aspartate 2B, GRM3: Glutamate receptor, metabotropic 3, GSK3B: Glycogen synthase kinase 3 beta, HLA: Major histocompatibility complex, HLA-A:
Major histocompatibility complex, class I, A, HRH1: Histamine receptor H1, HRH2: Histamine receptor H2, HRH3: Histamine receptor H3, HRH4: Hista-
mine receptor H4, HTR1A: 5-Hydroxytryptamine (serotonin) receptor 1A, HTR1B: 5-Hydroxytryptamine (serotonin) receptor 1B, HTR1D:
5-Hydroxytryptamine (serotonin) receptor 1D, HTR1E: 5-Hydroxytryptamine (serotonin) receptor 1E, HTR1F: 5-Hydroxytryptamine (serotonin) receptor 1F,
HTR2A: 5-Hydroxytryptamine (serotonin) receptor 2A, HTR2B: 5-Hydroxytryptamine (serotonin) receptor 2B, HTR2C: 5-Hydroxytryptamine (serotonin)
receptor 2C, HTR3A: 5-Hydroxytryptamine (serotonin) receptor 3A, HTR6: 5-Hydroxytryptamine (serotonin) receptor 6, HTR7:5-Hydroxytryptamine (sero-
tonin) receptor 7 (adenylate cyclase-coupled), HTT: Huntingtin, IL12B: Interleukin 12B (natural killer cell stimulatory factor 2, cytotoxic lymphocyte matura-
tion factor 2, p40), IL1RN: Interleukin 1 receptor antagonist, KCNE1: Potassium voltage-gated channel, Isk-related family, member 1, KCNE2: Potassium
voltage-gated channel, Isk-related family, member 2, KCNH: Potassium voltage-gated channel, subfamily H (eag-related), member 1-8, KCNH2: Potassium
voltage-gated channel, subfamily H (eag-related), member 2, KCNH6: Potassium voltage-gated channel, subfamily H (eag-related), member 6, KCNJ11:
Potassium inwardly-rectifying channel, subfamily J, member 11, KCNQ1: Potassium voltage-gated channel, KQT-like subfamily, member 1, LEP: Leptin,
LEPR: Leptin receptor, LPL: Lipoprotein lipase, NPY: Neuropeptide Y, PO N1: Paraoxonase 1, RGS2: Regulator of G-protein signaling 2, 24kDa, RGS4:
Regulator of G-protein signaling 4, SCN5A: Sodium channel, voltage-gated, type V, alpha subunit, SLC6A2: Solute carrier family 6 (neurotransmitter trans-
porter, noradrenalin), member 2, SLC6A4: Solute carrier family 6 (neurotransmitter transporter, serotonin), member 4, TNF: Tumor necrosis factor (TNF
superfamily, member 2), UGT1A3: UDP glucuronosyltransferase 1 family, polypeptide A3, UGT1A4: UDP glucuronosyltransferase 1 family, polypeptide A4.
(Generated with data from Cacabelos [25]).
of CYP2D6, and 23% of CYP3A4; 24% of antidepres-
sants are major substrates of CYP1A2 enzymes, 5% of
CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and
38% of CYP3A4; 7% of benzodiazepines are major
substrates of CYP2C19 enzymes, 20% of CYP2D6, and
95% of CYP3A4 [14]. Most CYP enzymes exhibit on-
togenic-, age-, sex-, circadian-, and ethnic-related dif-
ferences [26]. The practical consequence of this genetic
variation is that the same drug can be differentially me-
tabolized according to the genetic profile/expression
during each subject’s lifespan, and that knowing the
pharmacogenomic profile of an individual, his/her phar-
macodynamic response is potentially predictable to
some extent.
Among genes of the CYP superfamily with relevance
in the metabolism of psychotropic drugs, the CYP2D6,
CYP2C19, CYP2C9, and CYP3A4/5 genes deserve spe-
cial attention.
CYP2D6. CYP2D6 is a 4.38 kb gene with 9 exons
mapped on 22q13.2. Four RNA transcripts of 1190 -
1684 bp are expressed in the brain, liver, spleen and re-
productive system, where 4 major proteins of 48 - 55
kDa (439 - 494 aa) are identified. This protein is a trans-
port enzyme of the cytochrome P450 subfamily IID or
multigenic cytochrome P450 superfamily of mixed-
function monooxygenases which localizes to the endo-
plasmic reticulum and is known to metabolize as many
as 25% of commonly-prescribed drugs and over 60% of
current psychotropics. The gene is highly polymorphic in
the population. There are 141 CYP2D6 allelic variants,
of which −100C > T, −1023C > T, −1659G > A,
−1707delT, −1846G > A, −2549delA, −2613 −
2615delAGA, −2850C > T, −2988G > A, and −3183G >
A represent the 10 most important variants. Different

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 70
alleles result in the extensive, intermediate, poor, and
ultra-rapid metabolizer phenotypes, characterized by
normal, intermediate, decreased, and multiplied ability to
metabolize the enzyme’s substrates, respectively. P450
enzymes convert xenobiotics into electrophilic interme-
diates which are then conjugated by phase II enzymes to
hydrophilic derivatives that can be excreted. According
to the database of the World Guide for Drug Use and
Pharmacogenomics [25], 982 drugs are CYP2D6-related:
371 drugs are substrates, over 300 drugs are inhibitors,
and 18 drugs are CYP2D6 inducers.
Among healthy individuals, extensive metabolizers
(EMs) account for 55.71% of the population, whereas
intermediate metabolizers (IMs) are 34.7%, poor me-
tabolizers (PMs) 2.28%, and ultra-rapid metabolizers
(UMs) 7.31%. Remarkable interethnic differences exist
in the frequency of the PM and UM phenotypes among
different societies all over the world [4,27-29]. On aver-
age, approximately 6.28% of the world population be-
longs to the PM category. Europeans (7.86%), Polyne-
sians (7.27%), and Africans (6.73%) exhibit the highest
rate of PMs, whereas Orientals (0.94%) show the lowest
rate [27]. The frequency of PMs among Middle Eastern
populations, Asians, and Americans is in the range of 2%
- 3%. CYP2D6 gene duplications are relatively infre-
quent among Northern Europeans, but in East Africa the
frequency of alleles with duplication of CYP2D6 is as
high as 29% [30]. In Europe, there is a North-South gra-
dient in the frequency of PMs (6% - 12% of PMs in
Southern European countries, and 2% - 3% PMs in
Northern latitudes) [25]. In SCZ, EMs, IMs, PMs, and
UMs are 58.42%, 27.72%, 3.96%, and 9.9%, respectively,
with a 3% increase in the frequency of EMs, and a 7%
decrease in the frequency of IMs with respect to controls
in the Iberian population. In Alzheimer disease (AD),
EMs, IMs, PMs, and UMs are 56.38%, 27.66%, 7.45%,
and 8.51%, respectively, and in vascular dementia,
52.81%, 34.83%, 6.74%, and 5.62%, respectively (Fi-
gures 2 and 3). There is an accumulation of AD-related
genes of risk in PMs and UMs. EMs and IMs are the best
responders, and PMs and UMs are the worst responders
to pharmacological treatment. Patients with depression
show significant differences in the genotypic and pheno-
typic profiles as compared to controls and also with re-
spect to patients with psychosis, Parkinson’s disease, or
brain tumors. Patients with stroke show differences as
compared to patients with brain tumors, and both patients
with brain tumors or with cranial nerve neuropathies
differ in their CYP2D6 phenotype with regard to controls.
These geno-phenotypic profiles might be important in
Figure 2. CYP2D6 variants in dementia and schizophrenia. C: Controls; AD: Alzheimer disease; VD: Vascular dementia; SCZ:
Schizophrenia.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 71
CYP2D6 phenotypes in Dementia and Schizophrenia
EM IM PM UM
Figure 3. CYP2D6 phenotypes in dementia and schizophrenia. EM: Extensive Metabolizers;
IM: Intermediate Metabolizers; PM: Poor Metabolizers; UM: Ultra-rapid Metabolizers. C:
Controls; AD: Alzheimer disease; VD: Vascular dementia; SCZ: Schizophrenia.
the pathogenesis of some CNS disorders and in the thera-
peutic response to conventional psychotropic drugs as
well [2] (Figures 2 - 3).
CYP2C9. CYP2C9 is a gene (50.71 kb) with 9 exons
mapped on 10q24. An RNA transcript of 1860 bp is
mainly expressed in hepatocytes, where a protein of
55.63 kDa (490 aa) can be identified. Over 600 drugs are
CYP2C9-related, 311 acting as substrates (177 are major
substrates, 134 are minor substrates), 375 as inhibitors
(92 weak, 181 moderate, and 102 strong inhibitors), and
41 as inducers of the CYP2C9 enzyme [25]. There are
481 CYP2C9 SNPs. CYP2C9-*1/*1 EMs represent
60.56% of the healthy population; *1/*2 and *1/*3 IMs
18.78% and 13.62%, respectively (32.39% IMs); and
*2/*2, *2/*3, and *3/*3 PMs, 3.76%, 3.28%, and 0%,
respectively (7.04% PMs). No CYP2C9-*3/*3 cases
have been found in the control population; however, in
patients with depression, psychosis, and mental retarda-
tion the frequency of this genotype is 0.91%, 1.03%, and
1.37%, respectively (Figure 4). The frequency of PMs,
IMs, and PMs in the control population are 60.56%,
32.39%, and 7.04%, respectively, and in SCZ are 61.86%,
32.99%, and 5.15% (Figure 5). Significant variation has
been found in CYP2C9 genotypes among diverse brain
diseases [2] (Figures 4 - 5).The plethora of metabolizing
profiles in CNS disorders suggest a potential pathogenic
role of CYP2C9 in brain pathology and a very strong
role of the CYP2C9 enzyme on drugs with deleterious
effects on cerebrovascular function (e.g. NSAIDs) and
thromboembolic phenomena and/or bleeding (e.g. war-
farin, coumarinics).
CYP2C19. CYP2C19 is a gene (90.21 kb) with 9 ex-
ons mapped on 10q24.1q24.3. RNA transcripts of 1901
bp, 2395 bp, and 1417 bp are expressed in liver cells
where a protein of 55.93 kDa (490 aa) is identified.
Nearly 500 drugs are CYP2C19-related, 281 acting as
substrates (151 are major substrates, 130 are minor sub-
strates), 263 as inhibitors (72 weak, 127 moderate, and
64 strong inhibitors), and 23 as inducers of the CYP2C19
enzyme [25]. About 541 SNPs have been detected in the
CYP2C19 gene. The frequencies of the 3 major
CYP2C19 geno-phenotypes in the control population are
CYP2C19-*1/*1-EMs 68.54%, CYP2C19-*1/*2-IMs
30.05%, and CYP2C19-*2/*2-PMs 1.41%. In SCZ, EMs,
IMs, and PMs represent 76.29%, 22.68%, and 1.03%,
respectively (Figure 6). Minor variation has been re-
ported in different brain disorders [2].
CYP3A4/5. CYP3A4 is a gene (27.2 kb) with 13 ex-
ons mapped on 7q21.1. RNA transcripts of 2153 bp, 651
bp, 564 bp, 2318 bp and 2519 bp are expressed in intes-
tine, liver, prostate and other tissues where 4 protein
variants of 57.34 kDa (503 aa), 17.29 kDa (153 aa),
40.39 kDa (353 aa), and 47.99 kDa (420 aa) are identi-
fied. The human CYP3A locus contains the three
CYP3A genes (CYP3A4, CYP3A5 and CYP3A7), three
pseudogenes as well as a novel CYP3A gene termed
CYP3A43. The gene encodes a putative protein with
between 71.5% and 75.8% identity to the other CYP3A
proteins. The predominant hepatic form is CYP3A4, but
CYP3A5 contributes significantly to the total liver
CYP3A activity. This enzyme metabolizes over 1900
drugs, 1033 acting as substrates (897 are major substrates,
136 are minor substrates), 696 as inhibitors (118 weak,
437 moderate, and 141 strong inhibitors), and 241 as

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 72
CYP2C9 genot ype s/ ph e notypesin Demen ti a and Schizoph reni a
Figure 4. CYP2C9 geno/phenotypes in dementia and schizophrenia. EM: Extensive Metabo-
lizers; IM: Intermediate Metabolizers; PM: Poor Metabolizers. C: Controls; AD: Alzheimer
disease; VD: Vascular dementia; SCZ: Schizophrenia.
CYP2C9 phenotypesin Dementia and Schizophrenia
EM IM PM
Figure 5. CYP2C9 phenotypes in dementia and schizophrenia. EM: Extensive Metabolizers;
IM: Intermediate Metabolizers; PM: Poor Metabolizers. C: Controls; AD: Alzheimer disease;
VD: Vascular dementia; SCZ: Schizophrenia.
inducers of the CYP3A4 enzyme [25]. About 347 SNPs
have been identified in the CYP3A4 gene (CYP3A4*1A:
Wild-type), 25 of which are of clinical relevance; in a
Caucasian population, 82.75% are EMs (CYP3A5*3/*3),
15.88% are IMs (CYP3A5*1/*3), and 1.37% are UMs
(CYP3A5*1/*1). Unlike other human P450s (CYP2D6,
CYP2C19) there is no evidence of a “null” allele for
CYP3A4 [2].
CYP Clustering. The construction of a genetic map
integrating the most prevalent CYP2D6 + CYP2C19 +
CYP2C9 polymorphic variants in a trigenic cluster yields
82 different haplotype-like profiles. The most frequent
trigenic genotypes are *1*1-*1*1-*1*1 (25.70%),
*1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%),
*1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%),
*1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%).
These 82 trigenic genotypes represent 36 different phar-
macogenetic phenotypes. According to these trigenic

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 73
CYP2 C19 genotypes/ phenotyp esin Dementia a nd Schizophrenia
Figure 6. CYP2C19 geno/phenotypes in dementia and schizophrenia. EM: Extensive Metabo-
lizers; IM: Intermediate Metabolizers; PM: Poor Metabolizers. C: Controls; AD: Alzheimer
disease; VD: Vascular dementia; SCZ: Schizophrenia.
clusters, only 26.51% of the population show a pure
3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure
3IM, 0% are pure 3PM, and 0% are 1UM2PM (the worst
possible phenotype). This implies that only one-quarter
of the population processes normally the drugs which are
metabolized via CYP2D6, CYP2C9 and CYP2C19 (ap-
proximately 60% of the drugs of current use) [2,5,10,12].
2.4. Genes Encoding Drug Transporters
ABC genes, especially ABCB1 (ATP-binding cassette,
subfamily B, member 1; P-glycoprotein-1, P-gp1; Mul-
tidrug Resistance 1, MDR1) (7q21.12), ABCC1 (9q31.1),
ABCG2 (White1) (21q22.3), and other genes of this
family encode proteins which are essential for drug me-
tabolism and transport. The multidrug efflux transporters
P-gp, multidrug-resistance associated protein 4 (MRP4)
and breast cancer resistance protein (BCRP), located on
endothelial cells lining brain vasculature, play important
roles in limiting movement of substances into and en-
hancing their efflux from the brain. Transporters also
cooperate with Phase I/Phase II metabolism enzymes by
eliminating drug metabolites. Their major features are
their capacity to recognize drugs belonging to unrelated
pharmacological classes, and their redundancy, by which
a single molecule can act as a substrate for different
transporters. This ensures an efficient neuroprotection
against xenobiotic invasions. The pharmacological in-
duction of ABC gene expression is a mechanism of drug
interaction, which may affect substrates of the
up-regulated transporter, and overexpression of MDR
transporters confers resistance to anticancer agents and
CNS drugs [31,32]. Also of importance for CNS phar-
macogenomics are transporters encoded by genes of the
solute carrier superfamily (SLC) and solute carrier or-
ganic (SLCO) transporter family, responsible for the
transport of multiple endogenous and exogenous com-
pounds, including folate (SLC19A1), urea (SLC14A1,
SLC14A2), monoamines (SLC29A4, SLC22A3), ami-
noacids (SLC1A5, SLC3A1, SLC7A3, SLC7A9,
SLC38A1, SLC38A4, SLC38A5, SLC38A7, SLC43A2,
SLC45A1), nucleotides (SLC29A2, SLC29A3), fatty
acids (SLC27A1-6), neurotransmitters (SLC6A2 (nora-
drenaline transporter), SLC6A3 (dopamine transporter),
SLC6A4 (serotonin transporter, SERT), SLC6A5,
SLC6A6, SLC6A9, SLC6A11, SLC6A12, SLC6A14,
SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19),
glutamate (SLC1A6, SLC1A7), and others [24]. Some
organic anion transporters (OAT), which belong to the
solute carrier (SLC) 22A family, are also expressed at the
BBB, and regulate the excretion of endogenous and ex-
ogenous organic anions and cations [33]. The transport
of amino acids and di- and tripeptides is mediated by a
number of different transporter families, and the bulk of
oligopeptide transport is attributable to the activity of
members of the SLC15A superfamily (Peptide Trans-
porters 1 and 2 [SLC15A1 (PepT1) and SLC15A2
(PepT2), and Peptide/Histidine Transporters 1 and 2
[SLC15A4 (PHT1) and SLC15A3 (PHT2)]. ABC and
SLC transporters expressed at the BBB may cooperate to
regulate the passage of different molecules into the brain
[34]. Polymorphic variants in ABC and SLC genes may
also be associated with pathogenic events in CNS disor-
ders and drug-related safety and efficacy complications
[25].

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 74
2.5. Pleiotropic Genes
Apolipoprotein E (APOE) is a pathogenic gene in de-
mentia and the prototypical paradigm of a pleiotropic
gene with multifaceted activities in physiological and
pathological conditions, including cardiovascular disease,
dyslipidemia, atherosclerosis, stroke, and AD [2,6,14].
ApoE is consistently associated with the amyloid plaque
marker for AD. APOE-4 may influence AD pathology
interacting with APP metabolism and Aβ accumulation,
enhancing hyperphosphorylation of tau protein and NFT
formation, reducing choline acetyltransferase activity,
increasing oxidative processes, modifying inflammation-
related neuroimmunotrophic activity and glial activation,
altering lipid metabolism, lipid transport and membrane
biosynthesis in sprouting and synaptic remodeling, and
inducing neuronal apoptosis [35].
The distribution of APOE genotypes in the Iberian
Peninsula is as follows: APOE-2/2 0.32%, APOE-2/3
7.3%, APOE-2/4 1.27%, APOE-3/3 71.11%, APOE-3/4
18.41%, and APOE-4/4 1.59% (Figure 3). These fre-
quencies are very similar in Europe and in other Western
societies. There is a clear accumulation of APOE-4 car-
riers among patients with AD (APOE-3/4 30.30%;
APOE-4/4 6.06%) and vascular dementia (APOE-3/4
35.85%, APOE-4/4 6.57%) as compared to controls
(Figure 7). The distribution and frequencies of APOE
genotypes in AD also differ from those of patients with
anxiety, depression, psychosis, migraine, vascular en-
cephalopathy, and post-traumatic brain injury syndrome
[2,6,14] (Figure 3). Different APOE genotypes confer
specific phenotypic profiles to AD patients. Some of
these profiles may add risk or benefit when the patients
are treated with conventional drugs, and in many in-
stances the clinical phenotype demands the administra-
tion of additional drugs which increase the complexity of
therapeutic protocols. From studies designed to define
APOE-related AD phenotypes, several conclusions can
be drawn: 1) the age-at-onset is 5 - 10 years earlier in
approximately 80% of AD cases harboring the APOE-4/4
genotype; 2) the serum levels of ApoE are lowest in
APOE-4/4, intermediate in APOE-3/3 and APOE-3/4,
and highest in APOE-2/3 and APOE-2/4; 3) serum cho-
lesterol levels are higher in APOE-4/4 than in the other
genotypes; 4) HDL-cholesterol levels tend to be lower in
APOE-3 homozygotes than in APOE-4 allele carriers; 5)
LDL-cholesterol levels are systematically higher in
APOE-4/4 than in any other genotype; 6) triglyceride
levels are significantly lower in APOE-4/4; 7) nitric ox-
ide levels are slightly lower in APOE-4/4; 8) serum and
cerebrospinal fluid Aβ levels tend to differ between
APOE-4/4 and the other most frequent genotypes
(APOE-3/3, APOE-3/4); 9) blood histamine levels are
dramatically reduced in APOE-4/4 as compared with the
other genotypes; 10) brain atrophy is markedly increased
in APOE-4/4 > APOE-3/4 > APOE-3/3; 11) brain map-
ping activity shows a significant increase in slow wave
activity in APOE-4/4 from early stages of the disease; 12)
brain hemodynamics, as reflected by reduced brain blood
flow velocity and increased pulsatility and resistance
indices, is significantly worse in APOE-4/4 (and in
APOE-4 carriers in general, as compared with APOE-3
carriers); brain hypoperfusion and neocortical oxygena-
tion is also more deficient in APOE-4 carriers; 13) lym-
phocyte apoptosis is markedly enhanced in APOE-4 car-
riers; 14) cognitive deterioration is faster in APOE-4/4
Figure 7. APOE genotypes in dementia and schizophrenia.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 75
patients than in carriers of any other APOE genotype; 15)
in approximately 3% - 8% of the AD cases, the presence
of some dementia-related metabolic dysfunctions accu-
mulates more in APOE-4 carriers than in APOE-3 carri-
ers; 16) some behavioral disturbances, alterations in cir-
cadian rhythm patterns, and mood disorders are slightly
more frequent in APOE-4 carriers; 17) aortic and sys-
temic atherosclerosis is also more frequent in APOE-4
carriers; 18) liver metabolism and transaminase activity
also differ in APOE-4/4 with respect to other genotypes;
19) hypertension and other cardiovascular risk factors
also accumulate in APOE-4; and 20) APOE-4/4 carriers
are the poorest responders to conventional drugs. These
20 major phenotypic features clearly illustrate the bio-
logical disadvantage of APOE-4 homozygotes and the
potential consequences that these patients may experi-
ence when they receive pharmacological treatment for
AD and/or concomitant pathologies [2,4-6,9-12,35].
When APOE and CYP2D6 genotypes are integrated in
bigenic clusters and the APOE + CYP2D6-related thera-
peutic response to a combination therapy is analyzed in
AD patients, it becomes clear that the presence of the
APOE-4/4 genotype is able to convert pure CYP2D6*1/*1
extensive metabolizers into full poor responders to con-
ventional treatments, indicating the existence of a pow-
erful influence of the APOE-4 homozygous genotype on
the drug-metabolizing capacity of pure CYP2D6 exten-
sive metabolizers. In addition, a clear accumulation of
APOE-4/4 genotypes is observed among CYP2D6 poor
and ultra-rapid metabolizers [4,11].
3. GENOMICS OF SCHIZOPHRENIA
AND PSYCHOTIC DISORDERS
3.1. Structural Genomics
Genetic studies in SCZ have revealed the presence of
cytogenetic changes, chromosome anomalies and multi-
ple candidate genes potentially associated with psychosis
and related traits; and neurocognitive impairment was
found to be heritable in individuals with SCZ and their
relatives [36]. First-degree relatives of probands with
SCZ or bipolar disorder (BD) are at increased risk of
these disorders. Half-siblings have a significantly in-
creased risk, but substantially lower than that of full-
siblings. Heritability for SCZ and BD is 64% and 59%,
respectively. Shared environmental effects are small but
substantial (SCZ: 4.5%, 4.4% - 7.4%; BD: 3.4%, 2.3% -
6.2%) for both disorders. SCZ and BD partly share
common genetic determinants [37]. Linkage analysis of
SCZ in African-American families revealed that several
regions show a decrease in the evidence for linkage as
the definition broadens: 8q22.1 (rs911, 99.26 cM),
16q24.3 (rs1006547, 130.48 cM), and 20q13.2 (rs1022689,
81.73 cM). One region shows a substantial increase in
evidence for linkage, 11p15.2 (rs722317, 24.27 cM).
These linkage results overlap two broad, previously-
reported linkage regions: 8p23.3-p12, found in studies
sampling largely families of European ancestry; and
11p11.2-q22.3, reported by a study of African-American
families [38].
The genome-wide linkage scan analysis of 707 Euro-
pean-ancestry families identified suggestive evidence for
linkage on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1.
Genome-wide significant evidence for linkage was ob-
served on chromosome 10p12. Significant heterogeneity
was also observed on chromosome 22q11.1. Evidence
for linkage across family sets and analyses was most
consistent on chromosome 8p21, with a one-LOD sup-
port interval that does not include the candidate gene
NRG1, suggesting that one or more other susceptibility
loci might exist in the region [39]. Genome-wide sig-
nificant evidence for linkage for SCZ or schizoaffective
disorder was found in a region on chromosome 17q21 in
families of Mexican and Central American ancestry. A
region on chromosome 15q22-23 showed suggestive
evidence of linkage with this same phenotype [40].
The human genome is enriched in interspersed seg-
mental duplications that sensitize approximately 10% of
our genome to recurrent microdeletions and microdupli-
cations as a result of unequal crossing-over. Studies of
common complex genetic disease show that a subset of
these recurrent events plays an important role in autism,
SCZ, and epilepsy [41]. The advent of genome-wide
SNP and copy number variant (CNV) microarray tech-
nologies heralds identification of additional SCZ loci.
Over 200 genes, reported in about 2400 studies, have
been associated with SCZ during the past two decades;
however, it is likely that over 1000 genes might be in-
volved in SCZ pathogenesis through epistatic interaction
and epigenetic phenomena. Many of these associations
could not be replicated in different populations, as hap-
pens with many other multifactorial/complex disorders
[42]. Data suggest that these susceptibility genes influ-
ence the cortical information processing which charac-
terizes the schizophrenic phenotype. Aberrant postnatal
brain maturation is an essential mechanism underlying
the disease. Several candidate genes have been suggested,
with the strongest evidence for genes encoding dystro-
brevin binding protein 1 (DTNBP1), neuregulin 1
(NRG1), neuregulin 1 receptor (ERBB4) and disrupted
in SCZ1 (DISC1), as well as several neurotrophic factors.
These genes are involved in neuronal plasticity and also
play a role in adult neurogenesis [43].
Several studies of the dystrobrevin-binding protein 1
gene (DTNBP1), neuregulin 1 (NRG1), D-amino-acid
oxidase (DAO), DAO activator (DAOA, G72), and me-
tabotropic glutamate receptor 3 (GRM3) genes have
suggested an association between variants of these genes

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 76
and SCZ; however, several studies did not replicate as-
sociations of DTNBP1, NRG1, DAO, DAOA, and
GRM3 gene polymorphisms and SCZ [44]. Within the
last 2 years, a number of genome-wide association stud-
ies (GWAS) of SCZ and BD have been published [45-48].
These have produced stronger evidence for association to
specific risk loci than had earlier studies, specifically for
the zinc finger binding protein 804A (ZNF804A) locus in
SCZ and for the calcium channel, voltage-dependent, L
type, alpha 1C subunit (CACNA1C) and ankyrin 3, node
of Ranvier (ANK3) loci in BD. The ZNF804A and
CACNA1C loci appear to influence risk for both disor-
ders, a finding that supports the hypothesis that SCZ and
BD are not etiologically distinct. In the case of SCZ, a
number of rare copy number variants have also been de-
tected that have fairly large effect sizes on disease risk,
and that additionally influence risk of autism, mental
retardation, and other neurodevelopmental disorders. The
existing findings point to some likely pathophysiological
mechanisms but also challenge current concepts of dis-
ease classification [49]. A genome scan meta-analysis
(GSMA) was carried out on 32 independent genome-
wide linkage scan analyses that included 3255 pedigrees
with 7413 genotyped cases affected with SCZ or related
disorders. Suggestive evidence for linkage was observed
in two single bins, on chromosomes 5q (142 - 168 Mb)
and 2q (103 - 134 Mb). Genome-wide evidence for link-
age was detected on chromosome 2q (119 - 152 Mb)
when bin boundaries were shifted to the middle of the
previous bins. The primary analysis met empirical crite-
ria for “aggregate” genome-wide significance, indicating
that some or all of 10 bins are likely to contain loci
linked to SCZ, including regions of chromosomes 1, 2q,
3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22
studies of European-ancestry samples, suggestive evi-
dence for linkage was observed on chromosome 8p (16 -
33 Mb) [50]. In another GWAS, evidence was found for
association to genes reported in other GWAS data sets
(CACNA1C) or to closely-related family members of
those genes, including CSF2RB, CACNA1B and DGKI
[51].
A summary of genes (or pathological pathways) with
potential effect in SCZ pathogenesis is the major goal of
the present review in order to understand the complex
molecular mechanisms which might be responsible for
the clinical manifestations of one of the oldest diseases in
the constellation of mental illness.
3.2. Genes Potentially Associated with
Schizophrenia and Psychotic Disorders
ABCA13 (ATP-binding cassette, sub-family A (ABC1),
member 13). The lipid transporter gene ABCA13 is a
susceptibility factor for both SCZ and BD. SCZ and BD
are leading causes of morbidity across all populations,
with heritability estimates of approximately 80%, indi-
cating a substantial genetic component. Population ge-
netics and GWAS suggest an overlap of genetic risk fac-
tors between these illnesses. Knight et al. [52] rese-
quenced ABCA13 exons in cases with SCZ and controls.
Multiple rare coding variants were identified, including
one nonsense and nine missense mutations and com-
pound heterozygosity/homozygosity in 6% of cases.
Variants were genotyped in additional SCZ, bipolar, de-
pression and control cohorts, and the frequency of all
rare variants combined was greater than controls in SCZ
and BD. The population-attributable risk of these muta-
tions was 2.2% for SCZ and 4.0% for BD [52].
Abelson helper integration site 1 (AHI1). The Abel-
son helper integration site 1 (AHI1) gene locus on chro-
mosome 6q23.3 is among a group of candidate loci for
SCZ susceptibility that were initially identified by link-
age followed by linkage disequilibrium (LD) mapping,
and subsequent replication of the association in an inde-
pendent sample. The region contains two genes, AHI1
and C6orf217. Both genes and the neighboring phos-
phodiesterase 7B (PDE7B) may be considered candi-
dates for involvement in the genetic etiology of SCZ [53].
Of 14 SNPs tested (ATP2B2, HS3ST2, UNC5C, BAG3,
PDE7B, PAICS, PTGFRN, NR3C2, ZBTB20, ST6GAL2,
PIP5K1B, EPHA6, KCNH5, and AJAP1), only one
(rs9389370) in PDE7B (high-affinity cAMP-specific pho-
sphodiesterase 7B) showed significant evidence for as-
sociation with SCZ in a Japanese sample [54].
The AHI1 gene is required for both cerebellar and cor-
tical development in humans. According to Rivero et al.
[55], while the accelerated evolution of AHI1 in the hu-
man lineage indicates a role in cognitive function, a
linkage scan in large pedigrees identified AHI1 as a posi-
tional candidate for SCZ. These authors evaluated the
effect of AHI1 variation on the vulnerability to psychosis
in two samples from Spain and Germany. 29 SNPs lo-
cated in a genomic region including the AHI1 gene were
genotyped in the Ibero-German sample. rs7750586 and
rs911507, both located upstream of the AHI1 coding
region, were found to be associated with SCZ in the
analysis of genotypic and allelic frequencies. Several
other risk and protective haplotypes were also detected.
Joint analysis of both ethnic samples supported the asso-
ciation of rs7750586 and rs911507 with the risk for SCZ.
Adenylosuccinate synthase (ADSS) and ataxia te-
langiectasia (ATM) genes. The blood-derived RNA lev-
els of the adenylosuccinate synthase (ADSS) and ataxia
telangiectasia mutated (ATM) genes were found to be
down- and up-regulated, respectively, in schizophrenics
compared with controls, and ADSS and ATM were
among eight biomarker genes to discriminate schizo-
phrenics from normal controls. ADSS catalyzes the first
committed step of AMP synthesis, while ATM kinase

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 77
serves as a key signal transducer in the DNA dou-
ble-strand breaks response pathway. Studies with 6 SNPs
in the ADSS gene and 3 SNPs in the ATM gene did not
show significant difference in the genotype, allele, or
haplotype distributions in a Chinese population of SCZ
patients. Using the Multifactor Dimensionality Reduc-
tion (MDR) method, interactions among rs3102460 in
the ADSS gene and rs227061 and rs664143 in the ATM
gene revealed a significant association with SCZ with a
maximum testing accuracy of 60.4%, suggesting that the
combined effects of the polymorphisms in the ADSS and
ATM genes may confer susceptibility to the development
of SCZ in a Chinese population [56].
Adrenergic alpha-2A, receptor (ADRA2A). Several
lines of studies have shown the existence of an important
inhibitory mechanism for the control of water intake in-
volving adrenergic alpha-2A receptors. A human study
using patients with SCZ demonstrated an exacerbation of
polydipsia by the administration of clonidine, an ADR-
A2A-agonist, and a relief of polydipsia by mianserin, an
ADRA2A-antagonist, suggesting the involvement of the
central adrenergic system in the drinking behavior of
patients with SCZ. Based on these findings Yamaguchi et
al. [57] examined a possible association between the
C-1291G polymorphism in the promoter region of the
ADRA2A gene and polydipsia in SCZ using a Japanese
case-control sample. No significant association between
the ADRA2A C-1291G polymorphism and polydipsia
was found [57].
ALDHs and retinoic acid-related genes. Vitamin A
(retinol), the biologically active form of retinoic acid, has
been proposed as being involved in the pathogenesis of
SCZ. 18 SNPs in the regulatory and coding sequences of
7 genes involved in the synthesis, degradation and
transportation of retinoic acid, ALDH1A1, ALDH1A2,
ALDH1A3, CYP26A1, CYP26B1, CYP26C1 and trans-
thyretin (TTR) have been studied in SCZ. Association
analyses using both allelic and genotypic single-locus
tests revealed no significant association between the risk
for each of these genes and SCZ; however, analyses of
multiple-locus haplotypes indicated that the overall fre-
quency of rs4646642-rs4646580 of the ALDH1A2 gene
showed a significant difference between patients and
control subjects in the Chinese population [58].
Alpha- and beta-synuclein (SNCA, SNCB). Al-
pha-synuclein is expressed in the CNS. A high concen-
tration of alpha-synuclein in presynaptic terminals can
mimic the normal function of endogenous alpha-synu-
clein in regulating synaptic vesicle mobilization at nerve
terminals. Beta-synuclein protein is seen primarily in
brain tissue. Beta-synuclein may act as an inhibitor of
alpha-synuclein aggregation, which occurs in neurode-
generative diseases, such as Parkinson’s disease. Noori-
Daloii et al. [59] studied the changes of alpha- and
beta-synucleins in SCZ patients in relation to a control
group. The relative expression of alpha- and beta-synu-
cleins showed downregulation in patients in comparison
to the control group. Beta-synuclein mRNA expression
in the control group was significantly higher than that in
the patient group, but downregulation of alpha-synuclein
gene was not significant.
Angiotensin I converting enzyme (peptidyl-dipep-
tidase A) 1 (ACE). ACE variants are currently associ-
ated with cardiovascular and cerebrovascular risk factors
[5,10,11,35]. ACE insertion/deletion polymorphism was
also associated with SCZ and BD. DD genotype and D
allele distributions in bipolar patients and their first-de-
gree relatives were significantly higher than those of
SCZ patients, their relatives, and controls. In contrast, II
genotype and I allele were reduced in both the patient
groups and their relatives as compared with controls
[60].
AP-3 complex genes. Dysbindin is a component of
BLOC-1, which interacts with the adaptor protein (AP)-3
complex. Hashimoto et al. [61] examined a possible as-
sociation between 16 SNPs in the AP3 complex genes
and SCZ in Japanese patients. Nominal association be-
tween rs6688 in the AP3M1 gene and SCZ was initially
found, but this association was no longer positive after
correction for multiple testing, suggesting that AP3 com-
plex genes might not play a major role in the pathogene-
sis of SCZ in this population [61].
APOE and cholesterol transport genes. Several
studies suggest an accumulation of APOE-4 allele in
SCZ [35]. Disturbances in lipid homeostasis and myeli-
nation have been proposed in the pathophysiology of
SCZ and BD. Several antipsychotic and antidepressant
drugs increase lipid biosynthesis through activation of
the Sterol Regulatory Element-Binding Protein (SREBP)
transcription factors, which control the expression of
numerous genes involved in fatty acid and cholesterol
biosynthesis. Quantitative PCR and immunoblotting
were used to determine the level of lipid transport genes
in human glioblastoma (GaMg) exposed to clozapine,
olanzapine, haloperidol or imipramine. The effect of
some of these drugs was also investigated in human as-
trocytoma (CCF-STTG1), neuroblastoma (SH-SY5Y)
and hepatocellular carcinoma (HepG2) cells. Significant
transcriptional changes of cholesterol transport genes
(APOE, ABCA1, NPC1, NPC2, NPC1L1), which are
predominantly controlled by the liver X receptor (LXR;
NR1H2) transcription factor, have been detected. Stimu-
lation of cellular lipid biosynthesis by amphiphilic psy-
chotropic drugs is followed by a transcriptional activa-
tion of cholesterol transport and efflux pathways. Such
effects may be relevant for both therapeutic effects and
metabolic adverse effects of psychotropic drugs [62].

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 78
Apoptotic engulfment pathway. Apoptosis has been
speculated to be involved in SCZ. The apoptotic engulf-
ment pathway involving the MEGF10, GULP1, ABCA1
and ABCA7 genes has been investigated in SCZ. Nomi-
nally significant associations were found in GULP1
(rs2004888), ABCA1 (rs3858075) and ABCA7 genes. A
significant 2-marker (rs2242436*rs3858075) interaction
between the ABCA1 and ABCA7 genes and a 3-marker
interaction (rs246896*rs4522565*rs3858075) amongst
the MEGF10, GULP1 and ABCA1 genes were found in
different samples. The GULP1 gene and the apoptotic
engulfment pathway may be involved in SCZ in subjects
of European ancestry and multiple genes in the pathway
may interactively increase the risk of the disease [63].
Arginine vasopressin receptor 1A (AVPR1A). Ar-
ginine vasopressin (AVP) and the arginine vasopressin
receptor 1A gene contribute to memory function and a
range of social behaviors both in lower vertebrates and in
humans. Human promoter-region microsatellite repeat
regions (RS1 and RS3) in the AVPR1a gene region have
been associated with autism spectrum disorders, proso-
cial behavior and social cognition. Prepulse inhibition
(PPI) of the startle response to auditory stimuli is a
largely autonomic response that resonates with social
cognition in both animal models and humans. Reduced
PPI has been observed in disorders, including SCZ,
which are distinguished by deficits in social skills. Asso-
ciation studies between PPI and the AVPR1a RS1 and
RS repeat regions detected association between AVPR1a
promoter-region repeat length (especially RS3) and PPI.
Longer RS3 alleles were associated with greater levels of
prepulse inhibition. Using a short/long classification
scheme for the repeat regions, significant association was
also observed between all three PPI intervals (30, 60 and
120 ms) and both RS1 and RS3 polymorphisms. Longer
alleles, especially in male subjects, are associated with
significantly higher PPI response, consistent with a role
for the promoter repeat region in partially molding social
behavior in both animals and humans [64]. Molecular
genetic studies of AVPR1a and oxytocin (OXTR) recep-
tors have strengthened the evidence regarding the role of
these two neuropeptides in a range of normal and patho-
logical behaviors. Significant association has been shown
between both AVPR1a repeat regions and OXTR SNPs
with risk for autism. AVPR1a has also been linked to
eating behavior in both clinical and non-clinical groups.
Evidence also suggests that repeat variations in AVPR1a
are associated with two other social domains in Homo
sapiens: music and altruism. AVPR1a was associated
with dance and musical cognition, probably reflecting
the ancient role of this hormone in social interactions
executed by vocalization, ritual movement and dyadic
(mother-offspring) and group communication. Individual
differences have been observed in allocation of funds in
the dictator game, a laboratory game of pure altruism,
associated with length of the AVPR1a RS3 promoter-
region repeat [65]. Although molecular data are very
limited, it might be possible that dysfunctions in these
primitive neuropeptides involved in higher activities of
the CNS may influence autism/SCZ pathogenesis [66].
Arrestin, beta 2 (ARRB2). Tardive dyskinesia (TD)
may be associated with mediators or signaling complexes
behind DRD2, such as beta-arrestin-2 (ARRB2), an im-
portant mediator between DRD2 and serine-threonine
protein kinase (AKT) signal cascade. There is a signifi-
cant difference in the genotype distribution of ARRB2-
rs1045280 (Ser280Ser) between TD and non-TD SCZ
groups; and patients with the T allele have increased risk
of tardive dyskinesia [67].
BCL2-interacting killer (apoptosis-inducing) (BIK).
The Bcl2-interacting killer (BIK) gene interacts with
cellular and viral survival-promoting proteins, such as
Bcl-2, to enhance apoptosis. The BIK protein promotes
cell death in a manner analogous to Bcl-2-related death-
promoting proteins, Bax and Bak. Low Bcl-2 levels and
increased Bax/Bcl-2 ratio have been found in the tempo-
ral cortex of patients with SCZ. The BIK protein is sug-
gested to be a likely target for antiapoptotic proteins.
Nominal evidence for association of alleles rs926328 and
rs2235316 with SCZ was found in Japanese patients;
however, these associations were no longer positive after
correction for multiple testing [68].
Biogenesis of lysosome-related organelles complex
1 (BLOC-1). Biogenesis of lysosome-related organelles
complex 1 (BLOC-1) is a protein complex formed by the
products of eight distinct genes. Loss-of-function muta-
tions in two of these genes, DTNBP1 and BLOC1S3,
cause Hermansky-Pudlak syndrome, a human disorder
characterized by defective biogenesis of lysosome-re-
lated organelles. Haplotype variants within the same two
genes have been postulated to increase the risk of devel-
oping SCZ. In a fly model of BLOC-1 deficiency, mutant
flies lacking the conserved Blos1 subunit displayed eye
pigmentation defects due to abnormal pigment granules,
which are lysosome-related organelles, as well as ab-
normal glutamatergic transmission and behavior [69].
Brain-derived neurotrophic factor (BDNF). A vari-
ety of evidence suggests brain-derived neurotrophic fac-
tor (BDNF) as a candidate gene for SCZ. Several genetic
studies have shown a significant association between the
disease and certain SNPs within BDNF (specifically,
Val66Met and C270T). The functional microsatellite
marker BDNF-LCPR (BDNF-linked complex polymor-
phic region), which affects the expression level of BDNF,
is associated with BD. A meta-analysis of the two most
extensively studied polymorphisms (Val66Met and
C270T) revealed no association in single-marker or mul-
timarker analysis and no association of the Val66Met

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 79
polymorphism with SCZ, whereas C270T showed a trend
for association in a fixed model, but not in a random
model. These findings suggest that if BDNF is indeed
associated with SCZ, the A1 allele in BDNF-LCPR
would be the most promising candidate [70]. In a Tai-
wanese population no association was found between the
BDNF Val66Met polymorphism and SCZ; however, this
polymorphism may reduce psychopathology, in particu-
lar negative symptoms [71]. Allelic variation in the
BDNF gene has been associated with affective disorders,
but generally not SCZ. BDNF variants may help clarify
the status of schizoaffective disorder. Patients with
schizoaffective disorder and other affective disorders are
significantly more likely to carry two copies of the most
common BDNF haplotype (containing the valine allele
of the Val66Met polymorphism) compared with healthy
volunteers. When compared with SCZ patients, individu-
als with schizoaffective disorder are significantly more
likely to carry two copies of the common haplotype [72].
Defective BDNF has been proposed as a candidate
pathogenic mechanism in SCZ and dementia. BDNF
transcription is regulated during the protracted period of
human frontal cortex development. Expression of the
four most abundant alternative 5’ exons of the BDNF
gene (exons I, II, IV, and VI) has been studied in RNA
extracted from the prefrontal cortex. Expression of tran-
scripts I-IX and VI-IX was highest during infancy,
whereas that of transcript II-IX was lowest just after birth,
slowly increasing to reach a peak in toddlers. Transcript
IV-IX was significantly upregulated within the first year
of life, and was maintained at this level until school age.
Quantification of BDNF protein revealed that levels fol-
lowed a similar developmental pattern as transcript
IV-IX. In situ hybridization of mRNA in cortical sections
showed the highest expression in layers V and VI for all
four BDNF transcripts, whereas moderate expression
was observed in layers II and III. Although low expres-
sion of BDNF was observed in cortical layer IV, this
BDNF mRNA low-zone decreased in prominence with
age and showed an increase in neuronal mRNA localiza-
tion. These findings reported by Wong et al. [73] show
that dynamic regulation of BDNF expression occurs
through differential use of alternative promoters during
the development of the human prefrontal cortex, particu-
larly in the younger age groups, when the prefrontal cor-
tex is more plastic. Alterations in BDNF processing dur-
ing brain maturation cannot be neglected as a potential
mechanism for prefrontal cortex dysfunction in SCZ. The
levels of (pro)BDNF and receptor proteins, TrkB and p75,
are altered in the hippocampus in SCZ and mood disor-
der and polymorphisms in each gene influence protein
expression [74].
Neurodegenerative processes may be involved in the
pathogenesis of tardive dyskinesia (TD), and a growing
body of evidence suggests that BDNF plays a role in
both the antipsychotic effects and the pathogenesis of TD.
BDNF and glycogen synthase kinase (GSK)-3beta are
important in neuronal survival, and thus abnormal regu-
lation of BDNF and GSK-3beta may contribute to TD
pathophysiology. Park et al. [75] studied the relationship
between two polymorphisms, Val66Met in the BDNF
coding region and −50T/C in the GSK-3beta promoter,
and susceptibility to TD among a matched sample of
patients having SCZ with TD, patients with SCZ without
TD, and normal control subjects. PCR analysis revealed
no significant difference in the occurrence of the poly-
morphisms among the TD, non-TD, and control subjects,
but a significant interaction was observed among the
groups possessing BDNF Val allele in compound geno-
types. The schizophrenic subjects with the C/C GSK-3beta
genotype, who carry the Val allele of the BDNF gene, are
expected to have a decreased risk of developing neuro-
leptic-induced tardive dyskinesia [75].
Bromodomain containing 1 (BRD1). The bromodo-
main-containing protein 1 (BRD1) gene located at chro-
mosome 22q13.33 has been associated with SCZ and BD
susceptibility [76].
Calcium channel, voltage-dependent, L type, alpha
1C subunit (CACNA1C). Strong evidence of associa-
tion at the polymorphism rs1006737 (within CACNA1C,
the gene encoding the alpha-1C subunit of the L-type
voltage-gated calcium channel) with the risk of BD has
recently been reported in a meta-analysis of three ge-
nome-wide association studies of BD. The risk allele also
conferred increased risk for SCZ and recurrent major
depression with similar effect sizes to those previously
observed in BD. These findings are evidence of some
degree of overlap in the biological underpinnings of sus-
ceptibility to mental illness across the clinical spectrum
of mood and psychotic disorders [77]. A recent meta-
analysis of five case-control cohorts for major mood dis-
order, including over 13600 individuals genotyped on
high-density SNP arrays performed by the Bipolar Dis-
order Genome Study (BiGS) Consortium [78] identified
SNPs at 3p21.1 associated with major mood disorders
(rs2251219), with supportive evidence for association
observed in two out of three independent replication co-
horts. These results provide another example of a shared
genetic susceptibility locus for BD and major depressive
disorder [78].
To identify the neural system mechanism that explains
the genetic association between the CACNA1C gene and
psychiatric illness, Bigos et al. [79] used blood oxygena-
tion level-dependent (BOLD) functional magnetic reso-
nance imaging (fMRI) to measure brain activation in
circuitries related to bipolar disorder and schizophrenia
by comparing CACNA1C genotype groups among
healthy subjects. The risk-associated SNP rs1006737 in

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 80
CACNA1C predicted increased hippocampal activity
during emotional processing and increased prefrontal
activity during executive cognition. The risk-associated
SNP also predicted increased expression of CACNA1C
mRNA in the human brain. The risk-associated SNP in
CACNA1C maps to circuitries implicated in genetic risk
for bipolar disorder and schizophrenia. According to
Bigos and coworkers [79], its effects in human brain
expression implicate a molecular and neural system
mechanism for the clinical genetic association.
Calreticulin (CALR). Tissue-specific expression of
the calreticulin (CALR) gene in the gray matter is de-
velopment-dependent and coincides with the expression
of psychosis phenotypes. Farokhashtiani et al. [80] re-
ported instances of mutations within the core promoter
sequence of the gene in schizoaffective disorder. A
unique mutation at nucleotide −220 from the transcrip-
tion start site, located at a conserved genomic block in
the promoter region of the gene, co-occurs with the spec-
trum of psychoses. This mutation reverts the human
promoter sequence to the ancestral type observed in
chimpanzee, mouse, and several other species, implying
that the genomic block harboring nucleotide −220 may
be involved in the evolution of human-specific higher-
order functions of the brain that are ubiquitously im-
paired in psychoses.
Cannabinoid receptors. Two endocannabinoid re-
ceptors, CB1 and CB2 (CNR1, CNR2), are found in the
brain. The R63 allele of rs2501432 (R63Q), the C allele
of rs12744386 and the haplotype of the R63-C allele of
CB2 were significantly increased among patients with
SCZ. A significantly lower response to CB2 ligands in
cultured CHO cells transfected with the R63 allele com-
pared with those with Q63, and significantly lower CB2
receptor mRNA and protein levels found in human brain
with the CC and CT genotypes of rs12744386 compared
with TT genotype were observed. Endocannabinoid
function appears to be involved in SCZ. An increased
risk of SCZ might be present in people with low CB2
receptor function [81].
Cathepsin K (CTSK). Recent studies associate
cathepsin K with SCZ. Cathepsin K is capable of liber-
ating Met-enkephalin from beta-endorphin (beta-EP) in
vitro. To verify if this process might possibly contribute
to the pathogenesis of SCZ, post-mortem brains were
analyzed immunohistochemically for the presence and
co-localization of cathepsin K and beta-EP. In support of
a functional role of the observed formation of Met-en-
kephalin on the expense of beta-EP, increased numbers
of cathepsin K immunoreactive cells, but diminished
numbers of both beta-EP-positive cells and double-posi-
tive (cathepsin K/beta-EP) cells, were found in left and
right arcuate nucleus of schizophrenics. A reduced den-
sity of beta-EP-immunoreactive neuropil (fibers, nerve
terminals) was estimated in the left and right paraven-
tricular nucleus (PVN) of individuals with SCZ. Cathep-
sin K, which becomes up-regulated in its cerebral ex-
pression by neuroleptic treatment, might significantly
contribute to altered opioid levels in brains of schizo-
phrenics [82].
Cholecystokinin A receptor gene. Cholecystokinin A
receptor (CCKAR) has been implicated in the patho-
physiology of SCZ through its mediation of dopamine-
release in the CNS. Association between the CCKAR
gene and SCZ has been observed, especially between the
779T/C polymorphism and auditory hallucinations or
positive symptoms of SCZ. In the Japanese population,
no significant difference was observed in genotypic dis-
tributions or allelic frequencies between SCZ and con-
trols, although there was a trend for the association be-
tween the C allele of the polymorphism and hallucination
or hallucinatory-paranoid state [83].
Cholinergic receptor, nicotinic, alpha 7 (CHRNA7).
Multiple genetic linkage studies support the hypothesis
that the 15q14 chromosomal region contributes to the
etiology of SCZ. Among the putative candidate genes in
this area are the alpha7 nicotinic acetylcholine receptor
gene (CHRNA7) and its partial duplication, CHRFAM7A.
A large chromosomal segment including the CHRFAM7A
gene locus, but not the CHRNA7 locus, is deleted in
some individuals. The CHRFAM7A gene contains a
polymorphism consisting of a 2 base pair (2 bp) deletion
at position 497 - 498 bp of exon 6. The 2 bp polymor-
phism was associated with SCZ in African-Americans
and in Caucasians [84]. The rs3087454 SNP, located at
position −1831 bp in the upstream regulatory region of
CHRNA7, was significantly associated with SCZ in Af-
rican-American and non-Hispanic Caucasian case-con-
trol samples [85].
CLOCK. The clock genes have been reported to play
some roles in neural transmitter systems, including the
dopamine system, as well as to regulate circadian
rhythms. Abnormalities in both of these mechanisms are
thought to be involved in the pathophysiology of major
mental illness such as SCZ and mood disorders including
BP and major depressive disorder (MDD). Recent ge-
netic studies have reported that CLOCK, one of the clock
genes, might be associated with these psychiatric disor-
ders; however, association of CLOCK with SCZ might
be weak [86].
Clusterin (CLU). Clusterin (CLU) and clathrin as-
sembly lymphoid myeloid (CALM; PICALM) protein
are implicated in the function of neuronal synapses. Zhou
et al. [87] examined whether SNPs rs11136000 within
the CLU gene and rs3851179 within the CALM gene,
were associated with SCZ in the Chinese population.
Patients with SCZ and with family history showed a sig-
nificant increase of allele C frequency in rs11136000 in

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 81
comparison to normal controls. The C allele frequency
was also higher in patients with negative symptoms. In
contrast, allele and genotype frequencies of rs3851179
did not show significant differences between patients and
normal subjects or between patients with different sym-
ptoms.
CMYA5 (Cardiomyopathy-associated protein 5;
myosprym; tripartite motif-containing protein 76,
TRIM76). Chen et al. [88] found that in the CMYA5
gene, there were two non-synonymous markers,
rs3828611 and rs10043986, showing nominal signifi-
cance in both the CATIE (Clinical Antipsychotic Trials
of Intervention Effectiveness) and MGS-GAIN (molecu-
lar genetics of schizophrenia genome-wide association
study supported by the genetic association information
network) samples. In a combined analysis of both the
CATIE and MGS-GAIN samples, rs4704591 was identi-
fied as the most significant marker in the gene. Linkage
disequilibrium analyses indicated that these markers
were in low LD. CMYA5 was reported to be physically
interacting with the DTNBP1 gene, a promising candi-
date for schizophrenia, suggesting that CMYA5 may be
involved in the same biological pathway and process. In
a meta-analysis of all 23 replication samples (family
samples, 912 families with 4160 subjects; case-control
samples, 11380 cases and 15021 controls), the authors
found that the rs10043986 and rs4704591 markers are
significantly associated with SCZ. Haplotype condi-
tioned analyses indicated that the association signals ob-
served at these two markers are independent.
CNP. 2’,3’-Cyclic nucleotide 3’-phosphodiesterase
(CNP), another candidate gene for SCZ, participates in
oligodendrocyte function and in myelination. Five CNP
SNPs were investigated in a Chinese Han SCZ case-
control sample set with negative results. Factors includ-
ing gender, genotype, sub-diagnosis and antipsychotic
treatment were found not to contribute to the expression
regulation of the CNP gene in SCZ [89].
CNTNAP2, NRXN1, and the neurexin superfamily.
Heterozygous copy-number variants and SNPs of
CNTNAP2 and NRXN1, two distantly related members
of the neurexin superfamily, have been repeatedly asso-
ciated with a wide spectrum of neuropsychiatric disor-
ders, such as developmental language disorders, autism
spectrum disorders, epilepsy, and SCZ. Homozygous and
compound-heterozygous deletions and mutations via
molecular karyotyping and mutational screening in
CNTNAP2 and NRXN1 were identified in four patients
with severe mental retardation and variable features,
such as autistic behavior, epilepsy, and breathing anoma-
lies, phenotypically overlapping with Pitt-Hopkins syn-
drome. With a frequency of at least 1%, recessive defects
in CNTNAP2 appear to contribute significantly to severe
mental retardation. As known for fly Nrx-1, the CASPR2
ortholog Nrx-IV might also localize to synapses. Over-
expression of either protein can reorganize synaptic
morphology and induce increased density of active zones,
the synaptic domains of neurotransmitter release. Both
Nrx-I and Nrx-IV determine the level of the presynaptic
active-zone protein bruchpilot, indicating a possible
common molecular mechanism in Nrx-1 and Nrx-IV
mutant conditions [90].
Complexin-2. Because synaptic dysfunction plays a
key role in SCZ, the complexin 2 gene (CPLX2) was
examined by Begemann et al. [91] in the first phenotype-
based genetic association study (PGAS) of GRAS (Göt-
tingen Research Association for Schizophrenia). Six
SNPs, distributed over the whole CPLX2 gene, were
found to be highly associated with current cognition of
schizophrenic subjects but only marginally with premor-
bid intelligence. Correspondingly, in CPLX2-null mutant
mice, prominent cognitive loss of function was obtained
only in combination with a minor brain lesion applied
during puberty. In the human CPLX2 gene, 1 of the iden-
tified 6 cognition-relevant SNPs, rs3822674 in the 3’
untranslated region, was detected to influence mi-
croRNA-498 binding and gene expression. The same
marker was associated with differential expression of
CPLX2 in peripheral blood mononuclear cells. Results
extracted from this study suggest that cognitive perfor-
mance in schizophrenic patients may be modified by
CPLX2 variants modulating post-transcriptional gene
expression.
COMT. The catechol-O-methyltransferase (COMT)
gene, which is located in the 22q11.21 microdeletion, has
been considered as a candidate gene for SCZ due to its
ability to degrade catecholamines, including dopamine.
Human COMT contains three common polymorphisms
(A22S, A52T, and V108M), two of which (A22S and
V108M) render the protein susceptible to deactivation by
temperature or oxidation. The A52T mutation had no
significant effect on COMT structure. Residues 22 (al-
pha2) and 108 (alpha5) interact with each other and are
located in a polymorphic hotspot approximately 20 Ǻ
from the active site. Introduction of either the larger Ser
(22) or Met (108) tightens this interaction, pulling alpha2
and alpha5 toward each other and away from the protein
core. The V108M polymorphism rearranges active-site
residues in alpha5, beta3, and alpha6, increasing the
S-adenosylmethionine site solvent exposure. The A22S
mutation reorients alpha2, moving critical catechol-
binding residues away from the substrate-binding pocket.
The A22S and V108M polymorphisms evolved inde-
pendently in Northern European and Asian populations.
While the decreased activities of both A22S and V108M
COMT are associated with an increased risk for SCZ, the
V108M-induced destabilization is also linked with im-
proved cognitive function. Polymorphisms within this

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 82
hotspot may have evolved to regulate COMT activity,
and heterozygosity for either mutation may be advanta-
geous [92].
A common functional polymorphism (Val/Met) in
COMT that markedly affects enzyme activity has been
shown to affect executive cognition and the physiology
of the prefrontal cortex in humans. The high activity Val
allele slightly increases risk for SCZ through its effect on
dopamine-mediated prefrontal information processing.
The Val/Met polymorphism has become the most widely
studied polymorphism in psychiatry [93]. No statistically
significant differences were found in allele or genotype
frequencies between patient and normal control subjects,
although a nonsignificant over-representation of the Val
allele has been detected in Han Chinese patients with
SCZ. The meta-analysis of all published population-
based association studies showed statistically significant
evidence for heterogeneity among the group of studies.
Stratification of the studies by ethnicity of the samples
yielded no significant evidence for an association with
the Val allele in the Asian population [94,95].
The functional SNP Val108/158Met (rs4680) and hap-
lotypes rs737865-rs4680-rs165599 in COMT have been
extensively examined for association to SCZ; however,
results of replication studies have been inconsistent.
Okochi et al. [96] performed a mutation scan to detect
the existence of potent functional variants in the
5’-flanking and exon regions, and conducted a gene-
based case-control study between tagging SNPs in
COMT [19 SNPs including six possible functional SNPs
(rs2075507, rs737865, rs4680, rs165599, rs165849)] and
SCZ in the Japanese population. A meta-analysis of 5
functional SNPs and haplotypes (rs737865-rs4680-
rs165599) was also carried out. No novel functional
variant was detected in the mutation scan and no associa-
tion was found between these tagging SNPs in COMT
and Japanese SCZ. No evidence was found for an asso-
ciation between Val108/158Met polymorphisms, rs6267,
rs165599, and haplotypes (rs7378655-rs4680-rs165599)
and SCZ, although rs2075507 and rs737865 showed
trends for significance in allele-wise analyses [96].
COMT impacts the regulation of dopamine neuronal
activity in the brainstem, which is associated with psy-
chosis [97]. The rs362204 polymorphism shows associa-
tion with SCZ in different populations [97,98] and
rs6267 showed an association with reduced risk of SCZ
[99]. There is an association between the COMT gene
and violent behavior in Chinese schizophrenics. The
haplotypes A-A-G and G-G-A may be used to predict
violent behavior in schizophrenics [100]. COMT geno-
type contributes to cognitive flexibility, a fundamental
cognitive ability that potentially influences an individ-
ual’s performance in a variety of other neurocognitive
tasks. COMT genotype was significantly associated with
signal discrimination index d’ in SCZ. The Val/Val
genotype was associated with the highest and the
Met/Met genotype with the lowest scores; heterozygous
individuals displayed an intermediate performance [101].
The [oxy-Hb] increase in the Met carriers during the
verbal fluency task was significantly greater than that in
the Val/Val individuals in the frontopolar prefrontal cor-
tex of patients with SCZ, although neither medication
nor clinical symptoms differed significantly between the
two subgroups [102].
The Val108/158Met (rs4680) SNP in the COMT gene
is specifically related to impairments in executive func-
tioning. A different genomic region composed of three
SNPs (rs737865, rs4680, rs165599) within the COMT
gene has been reported to be significantly associated
with SCZ in Ashkenazi Jews, but not in other popula-
tions. In the Taiwanese population, the A allele of
rs165599 was transmitted preferentially to the affected
individuals, and significantly associated with a later age
of onset, more severe delusion/hallucination symptom
dimension, and poorer performance in the CPT. The tri-
ple SNP haplotypes did not reveal any significant asso-
ciation with SCZ or neurocognitive function [103]. Ac-
cording to these results, the SNP rs165599, which has
been mapped to the 3’-UTR region of the COMT gene,
was significantly associated with SCZ, and possibly as-
sociated with the age of onset, delusion/hallucination
symptom dimension, and CPT performance. Therefore,
COMT may contribute to the genetic risk for SCZ not
through the Val108/158Met polymorphism, but through
other variants that are situated 3’ to this region [103].
Liao et al. [104] examined the relations of genetic
variants in COMT, including rs737865 in intron 1,
rs4680 in exon 4 (Val158Met) and downstream rs165599,
to SCZ and its related neurocognitive functions in fami-
lies of patients with SCZ. The genotypes of rs4680 were
associated with both the Wisconsin Card Sorting Test
(WCST) and Continuous Performance Test (CPT) per-
formance scores in these families, but not with SCZ per
se in either whole sample or subgroup analyses. The
other two SNPs were differentially associated with the
two tasks. For WCST indexes, only rs737865 exhibited
moderate associations. For CPT indexes, rs737865 ex-
hibited association for the subgroup with deficit on CPT
reaction time, whereas rs165599 exhibited association
for the subgroup with deficit on CPT d’ as well as quan-
titative undegraded d’. These results suggest that COMT
variants might be involved in modulation of neurocogni-
tive functions, conferring increased risk for SCZ [104].
Some studies revealed potential epistatic effects of two
intronic SNPs located in the COMT and aldehyde dehy-
drogenase 3B1 (ALDH3B1) genes, which conferred ge-
netic risk to paranoid SCZ. Among the individuals car-
rying the rs3751082 A allele in the ALDH3B1 gene, the

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 83
rs4633 T allele in the COMT gene was associated with
susceptibility to paranoid SCZ, development of halluci-
nation, delay of P300 latency, and increased expression
of the COMT gene; however, the rs4633 T allele did not
show any association in the rs3751082 G/G genotype
carriers [105].
CSF2RB (Colony stimulating factor 2 receptor, beta,
low-affinity (granulocyte-macrophage)). CSF2RB en-
codes the protein which is the common β chain of the
high affinity receptor for IL-3, IL-5 and CSF. It locates in
the linkage region 22q13.1 of both bipolar disorder and
SCZ, and is expressed in most cells. Chen et al. [106]
carried out a large-scale case-control study to test the
association between CSF2RB and three major mental
disorders in the Chinese Han population. Seven SNPs
were genotyped in 1140 bipolar affective disorder pa-
tients (including 645 type I bipolar affective disorder
patients), 1140 schizophrenia patients, 1139 major de-
pressive disorder patients and 1140 healthy controls.
Three SNPs were found to be associated with both SCZ
and major depressive disorder. Haplotype association
analysis revealed one protective haplotype for SCZ and
for MDD and one risk haplotype for SCZ and for MDD.
These results support CSF2RB as a risk factor common
to both SCZ and major depression in the Chinese Han
population.
CTLA4 (Cytotoxic T-lymphocyte-associated pro-
tein 4). Some studies have reported that the cytotoxic T
lymphocyte antigen-4 (CTLA-4) gene, which is related
to immunological functions such as T-cell regulation, is
associated with psychiatric disorders. Liu et al. [107]
studied the relationship between CTLA-4 and three ma-
jor psychiatric disorders, SCZ, major depressive disorder
and bipolar disorder in the Chinese Han population. They
screened 6 tag SNPs (rs231777, rs231775, rs231779,
rs3087243, rs5742909, rs16840252) in the CTLA-4 gene,
and found that rs231779 conferred a risk for SCZ, major
depressive disorder, and bipolar disorder. rs231777 and
rs16840252 had a significant association with SCZ, and
rs231777 had significant association with bipolar disor-
der; however, after 10000 permutations, only rs231779
remained significant. These results led the Chinese au-
thors to conclude that shared common risk factors for
SCZ, major depressive disorder and bipolar disorder ex-
ist in the CTLA-4 gene in the Chinese Han population.
CYP3A4 and CYP3A5. Two-marker haplotypes cov-
ering components CYP3A41G and CYP3A53 were ob-
served to be significantly associated with SCZ in Chi-
nese patients [108].
D-Amino acid oxidase activator (DAOA, G72). The
DAOA gene locus on chromosome 13q34 has been im-
plicated in the etiology of SCZ. 3 SNPs (rs778294,
rs779293 and rs3918342) have been identified in this
region, and two of them (rs778293, rs3918342) have
shown significant transmission disequilibrium and a
highly significant under-transmission between haplotype
CAT and SCZ. G72 is one of the most widely tested
genes for association with SCZ. As G72 activates the
D-amino acid oxidase (DAO), G72 is termed D-amino
acid oxidase activator (DAOA). Ohi et al. [109] found
nominal evidence for association of alleles M22/
rs778293, M23/rs3918342 and M24/rs1421292, and the
genotype of M22/rs778293 with SCZ, although there
was no association of allele or genotype in the other five
SNPs. They also found nominal haplotypic association,
including M15/rs2391191 and M19/rs778294, with SCZ;
however, these associations were no longer positive after
correction for multiple testing, which suggests that G72
might not play a major role in the risk for SCZ in the
Japanese population [109]. Association of the G72/G30
locus with SCZ and BD has been reported in several
studies. The G72/G30 locus spans a broad region of
chromosome 13q. One meta-analysis of published asso-
ciation studies shows highly significant evidence of as-
sociation between nucleotide variations in the G72/ G30
region and SCZ, along with compelling evidence of as-
sociation with BD [110]. This locus has been associated
with panic disorder, SCZ, and BD, especially the 3 SNPs
rs2391191, rs3918341, and rs1935062, with controver-
sial results [111]. G72 is an activator of D-amino acid
oxidase (DAO), supporting the glutamate dysfunction
hypothesis of SCZ. G72 mRNA is poorly expressed in a
variety of human tissues (e.g. adult brain, amygdala,
caudate nucleus, fetal brain, spinal cord and testis) from
human cell lines or SCZ/control post-mortem BA10
samples. The lack of demonstrable G72 expression in
relevant brain regions does not support a role for G72 in
modulation of DAO activity and the pathology of SCZ
via a DAO-mediated mechanism. In silico analysis sug-
gests that G72 is not robustly expressed and that the
transcript is potentially labile [112].
Disrupted-in-schizophrenia-1 (DISC1). The dis-
rupted-in-schizophrenia-1 (DISC1) locus is located at the
breakpoint of a balanced t (1;11) (q42.1; q14.3) chromo-
somal translocation in a large and unique Scottish family.
This translocation segregates in a highly statistically sig-
nificant manner with a broad diagnosis of psychiatric
illness, including SCZ, BD and major depression, as well
as with a narrow diagnosis of SCZ alone. Two novel
genes were identified at this locus and due to the high
prevalence of SCZ in this family, they were named dis-
rupted-in-schizophrenia-1 (DISC1) and disrupted-inschi-
zophrenia-2 (DISC2). DISC1 encodes a novel multi-
functional scaffold protein, whereas DISC2 is a putative
noncoding RNA gene antisense to DISC1. A number of
independent genetic linkage and association studies in
diverse populations support the original linkage findings
in the Scottish family and genetic evidence now impli-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 84
cates the DISC locus in susceptibility to SCZ, schizoaf-
fective disorder, BD and major depression as well as
various cognitive traits. DISC1 is a hub protein in a mul-
tidimensional risk pathway for major mental illness [113].
Many alternatively spliced transcripts were identified,
including groups lacking exon 3 (Delta3), exons 7 and 8
(Delta7Delta8), an exon 3 insertion variant (extra short
variant-1, Esv1), and intergenic splicing between
TSNAX and DISC1. Isoforms Delta7Delta8, Esv1, and
Delta3, which encode truncated DISC1 proteins, were
expressed more abundantly during fetal development
than during postnatal ages, and their expression was
higher in the hippocampus of patients with SCZ. SCZ
risk-associated polymorphisms [non-synonymous SNPs
rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and
rs821597] were associated with the expression of Delta3
and Delta7Delta8 [114]. An inherited 2.07 Mb microdu-
plication in 1q42.2 was identified in two brothers with
autism and mild mental retardation in Belgium. The du-
plication contains seven genes, including the DISC1
gene which has been associated to SCZ, BD, autism and
Asperger syndrome [115]. DISC1 regulates neuronal
migration and differentiation during mammalian brain
development. Enomoto et al. [116] reported that DISC1
interacts with the actin-binding protein girdin to regulate
axonal development. Dentate granule cells (DGCs) in
girdin-deficient neonatal mice exhibit deficits in axonal
sprouting in the cornu ammonis 3 region of the hippo-
campus. Girdin deficiency, RNA interference-mediated
knockdown, and inhibition of the DISC1/girdin interac-
tion lead to overextended migration and mispositioning
of the DGCs resulting in profound cytoarchitectural dis-
organization of the DG. These findings identify girdin as
an intrinsic factor in postnatal development of the DG
and provide insights into the critical role of the
DISC1/girdin interaction in postnatal neurogenesis in the
DG. DISC1 suppression in newborn neurons of the adult
hippocampus leads to overactivated signaling of AKT,
another SCZ susceptibility gene. Mechanistically, DISC1
directly interacts with KIAA1212, an AKT-binding part-
ner that enhances AKT signaling in the absence of
DISC1, and DISC1 binding to KIAA1212 prevents AKT
activation in vitro. Multiple genetic manipulations to
enhance AKT signaling in adult-born neurons in vivo
exhibit similar defects to DISC1 suppression in neuronal
development, which can be rescued by pharmacological
inhibition of mammalian target of rapamycin (mTOR),
an AKT downstream effector. The AKT-mTOR signaling
pathway acts as a critical DISC1 target in regulating
neuronal development [117].
To elucidate how DISC1 confers susceptibility to psy-
chiatric disorders, identification of the molecules, which
bind to the domain close to the translocation breakpoint
in the DISC1 gene, was performed and fasciculation and
elongation protein zeta-1 (Fez1), a novel DISC1-inter-
acting protein, termed DISC1-binding zinc-finger protein
(DBZ), and Kendrin were identified. The DISC1-Fez1
interaction is up-regulated by nerve growth factor (NGF)
and involved in neurite extension. Transient dissociation
of the DISC1-DBZ interaction by pituitary adenylate
cyclase-activating polypeptide (PACAP) causes neurite
extension. SNP association studies have shown the rela-
tion of the Fez1, PACAP and PACAP receptor (PAC1)
genes to SCZ. In SCZ with DISC1 translocation carrier,
the DISC1-Fez1 and DISC1-DBZ interaction is disrupted,
and it is likely that neural circuit formation remains im-
mature, suggesting that SCZ is a neurodevelopmental
disease. The DISC1-Kendrin interaction is suggested to
be involved in microtubule network formation and an
association between SNPs of the Kendrin gene and bipo-
lar disease has also been suggested in a Japanese popula-
tion [118].
DISC1 interacts directly with phosphodiesterase 4B
(PDE4B), an independently identified risk factor for SCZ.
DISC1-PDE4B complexes are therefore likely to be in-
volved in molecular mechanisms underlying psychiatric
illness. PDE4B hydrolyzes cAMP, and DISC1 may
regulate cAMP signaling through modulating PDE4B
activity. There is evidence that expression of both genes
is altered in some psychiatric patients. DISC1 missense
mutations that give rise to phenotypes related to SCZ and
depression in mice are located within binding sites for
PDE4B. These mutations reduce the association between
DISC1 and PDE4B, and one results in reduced brain
PDE4B activity. Altered DISC1-PDE4B interaction may
thus underlie the symptoms of some cases of SCZ and
depression [119]. DISC1 protein binding partners include
the nuclear distribution factor E homologs (NDE1 and
NDEL1), LIS1, and phosphodiesterases 4B and 4D
(PDE4B and PDE4D). NDE1, NDEL1 and LIS1, to-
gether with their binding partner dynein, associate with
DISC1, PDE4B and PDE4D within the cell, and provide
evidence that this complex is present at the centrosome.
LIS1, NDEL1, DISC1, NDE1, and PDE4B are localized
at synapses in cultured neurons. NDE1 is phosphorylated
by cAMP-dependent protein kinase A (PKA), whose
activity is, in turn, regulated by the cAMP hydrolysis
activity of phosphodiesterases, including PDE4. DISC1
might act as an assembly scaffold for all of these proteins
and the NDE1/NDEL1/LIS1/dynein complex might be
modulated by cAMP levels via PKA and PDE4 [120].
A DISC1 haplotype, HEP3, and an NDE1 spanning
tag haplotype are associated with SCZ in Finnish fami-
lies. Tomppo et al. [121] identified three SNPs as being
associated with SCZ in PDE4D (rs1120303), PDE4B
(rs7412571), and NDEL1 (rs17806986). Greater signifi-
cance was observed with allelic haplotypes of PDE4D,
PDE4B, and NDEL1 that increased or decreased SCZ

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 85
susceptibility, highlighting the potential importance of
DISC1-related molecular pathways in the etiology of
SCZ and other major mental illnesses [121].
DISC1 is expressed in cranial neural crest (CNC) cells.
Loss of Disc1 resulted in persistent CNC cell medial
migration, dorsal to the developing neural epithelium,
and hindered migration away from the region dorsal to
the neural rod. The failure of CNC cells to migrate away
from the neural rod correlated with the enhanced expres-
sion of two transcription factors, foxd3 and sox10. These
transcription factors have many functions in CNC cells,
including the maintenance of precursor pools, timing of
migration onset, and the induction of cell differentiation.
DISC1 functions in the transcriptional repression of
foxd3 and sox10, thus mediating CNC cell migration and
differentiation [122].
DISC1 is widely expressed in cortical and limbic re-
gions. Association between the DISC1 Ser704Cys poly-
morphism and volumetric measurements for a broad
range of fronto-parietal, temporal, and limbic-paralimbic
regions was studied in Japanese patients with SCZ using
magnetic resonance imaging. The Cys carriers had sig-
nificantly larger volumes of the medial superior frontal
gyrus and shorter insular cortex than the Ser homozy-
gotes, but only in healthy comparison subjects. The Cys
carriers tended to have a smaller supramarginal gyrus
than the Ser homozygotes in SCZ patients, but not in
healthy comparison subjects. The right medial superior
frontal gyrus volume was significantly correlated with
daily dosage of antipsychotic medication in Ser homo-
zygote SCZ patients. These different genotype effects of
the DISC1 Ser704Cys polymorphism on the brain mor-
phology in SCZ suggest that variation in the DISC1 gene
might be involved in the neurobiology of SCZ [123].
Schumacher et al. [124] found evidence for a common
SCZ risk interval within DISC1 intron 4 - 6.
DNA methyltransferases (DNMTs). Aberrant DNA
methylation may be involved in the development of SCZ.
DNA methyltransferase 3B (DNMT3B) is the key me-
thyltransferase in DNA methylation regulations. Case-
control and family-based studies were performed through
genotyping two tag SNPs (rs2424908 and rs6119954)
covering the whole DNMT3B gene. The frequency of G
allele of rs6119954 was significantly higher in SCZ.
Genotype distribution of rs6119954 was significantly
different between patients and controls. A haplotype-wise
analysis revealed a higher frequency of the T-G
(rs2424908-rs6119954) haplotype in SCZ. In the trans-
mission disequilibrium test analysis, the G allele of
rs6119954 was preferentially transmitted in the trios.
According to these findings reported by Zhang et al.
[125] in Chinese patients, DNMT3B may be a candidate
gene for susceptibility to early onset SCZ. In SCZ, a
functional downregulation of the prefrontal cortex
GABAergic neuronal system is mediated by a promoter
hypermethylation, presumably catalyzed by an increase
in DNA-methyltransferase-1 (DNMT-1) expression. This
promoter hypermethylation may be mediated not only by
DNMT-1 but also by an entire family of de novo
DNA-methyltransferases, such as DNA-methyltrans-
ferase-3a (DNMT-3a) and -3b (DNMT-3b). There is an
overexpression of DNMT-3a and DNMT-3b in Brod-
mann’s area 10 (BA10) and in the caudate nucleus and
putamen of SCZ brains. DNMT-3a and DNMT-1 are
expressed and co-localize in distinct GABAergic neuron
populations whereas DNMT-3b mRNA is virtually un-
detectable. Unlike DNMT-1, which is frequently overex-
pressed in telencephalic GABAergic neurons of SCZ,
DNMT-3a mRNA is overexpressed only in layer I and II
GABAergic interneurons of BA10. DNMT-1 and DNMT-
3a mRNAs are also overexpressed in peripheral blood
lymphocytes of SCZ patients. The upregulation of
DNMT-1 and to a lesser extent that of DNMT-3a mRNA
in lymphocytes of SCZ supports the concept that this
readily available peripheral cell type can express an epi-
genetic variation of specific biomarkers relevant to SCZ
morbidity [126].
Dopamine-Related Genes
DARPP-32 (PPP1R1B). Recent findings have
highlighted the importance of DARPP-32 (dopa-
mine- and cAMP-regulated phosphoprotein, 32
kDa), a key regulatory molecule in the dopaminer-
gic signaling pathway for dopamine-related phenol-
types such as antisocial behavior, drug addiction
and SCZ. Reuter et al. [127] reported the first study
investigating the role of the DARPP-32 gene for
personality. In a sample of healthy German Cauca-
sian subjects they found a significant association
between rs907094 and anger. Carriers of the
T-allele showed significantly higher anger scores
than participants without a T-allele. A negative as-
sociation between ANGER scores and the volume
of the left amygdala was also detected [127].
Dopamine beta-hydroxylase. The SNP rs1108580
A/G in DBH has been associated with SCZ [98].
Dopamine transporter (DAT; SLC6A3) 3’ UTR
VNTR. Dopamine has a crucial role in the modula-
tion of neurocognitive function, and synaptic do-
pamine activity is normally regulated by the dopa-
mine transporter (DAT) and catechol-O-methyl-
transferase (COMT). Altered dopamine function is
a key pathophysiological feature of SCZ. Prata et al.
[128] examined epistasis between the DAT 3’ UTR
variable number of tandem repeats (VNTR) and

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 86
COMT Val158Met polymorphisms on brain activa-
tion during executive function in SCZ. There was a
significant COMT × DAT non-additive interaction
effect on activation in the left supramarginal gyrus.
In this region, relatively increased activation was
detected only when COMT Met-158/Met-158 sub-
jects also carried the 9-repeat DAT allele, or when,
reversely, Val-158/Val-158 subjects carried the
10/10-repeat genotype. There was also a significant
diagnosis × COMT × DAT non-additive interaction
in the right orbital gyrus. Greater activation was
only associated with a 9-repeat allele and Val-158
conjunction, and with a 10-repeat and Met-158
conjunction. COMT and DAT genes interact non-
additively to modulate cortical function during ex-
ecutive processing, and this effect is significantly
altered in SCZ, which may reflect abnormal dopa-
mine function in the disorder [128]. The dopamine
transporter plays a key role in the regulation of cen-
tral dopaminergic transmission, which modulates
cognitive processing. The effect of a polymorphism
in the dopamine transporter gene (the variable
number of tandem repeats in the 3’ untranslated re-
gion) (3’UTR VNTR) on brain function during ex-
ecutive processing has been studied in healthy vol-
unteers and patients with SCZ. The 10-repeat allele
was associated with greater activation than the
9-repeat allele in the left anterior insula and right
caudate nucleus. Insular, cingulate, and striatal
function during an executive task is normally mo-
dulated by variation in the dopamine transporter
gene. Its effect on activation in the dorsolateral pre-
frontal cortex and ventral striatum is altered in pa-
tients with SCZ. This may reflect altered dopamine
function in these regions in SCZ [129].
Dopamine receptor D2 (DRD2). 16 Polymor-
phisms from three genes, dopamine receptor D2
(DRD2), COMT and BDNF, which are involved in
the dopaminergic pathways, and which have been
reported to be associated with susceptibility to SCZ
and response to antipsychotic therapy, were inves-
tigated in SCZ. Initial significant associations of
two SNPs for DRD2 (rs11608185, rs6275), and one
SNP in the COMT gene (rs4680) were found, but
not after correction for multiple comparisons, indi-
cating a weak association of individual markers of
DRD2 and COMT with SCZ. Multifactor-dimen-
sionality reduction analysis suggested a two-loci
model (rs6275/DRD2 and rs4680/COMT) as the
best model for gene-gene interaction with 90%
cross-validation consistency and 42.42% prediction
error in predicting disease risk among SCZ patients
[130].
Dopamine D4 receptor (DRD4). Associations have
been reported between the variable number of tan-
dem repeat (VNTR) polymorphisms in exon 3 of
the dopamine D4 receptor (DRD4) gene and multi-
ple psychiatric illnesses/traits. The size of allele
“7R” is less frequent (0.5%) in Japanese than in
Caucasian populations (20%). The most common
4R variant is considered to be the ancestral haplo-
type. In a gene tree of VNTR constructed on the ba-
sis of this inferred ancestral haplotype, the allele 7R
has five descendent haplotypes in relatively long
lineage, where genetic drift can have major influ-
ence. No evidence of association between the allele
7R and SCZ was found in the Japanese population
[131]. Tardive dyskinesia (TD) is a side-effect of
chronic antipsychotic medication exposure. Ab-
normalities in dopaminergic activity in the ni-
gro-striatal system have most often been suggested
to be involved because the agents that cause TD
share in common potent antagonism of dopamine
D2 receptors (DRD2). A number of studies have
focused on the association of dopamine system
gene polymorphisms and TD, with the most consis-
tent findings being an association between TD and
the Ser9Gly polymorphism of the DRD3 gene and
the TaqIA site 3’ of the DRD2 gene. A haplotype
containing rs3732782, rs905568, and rs7620754 in
the 5’ region of DRD3 was associated with TD di-
agnosis [132]. The DRD4 gene codes for the third
member of the D2-like dopamine receptor family,
and the VNTR polymorphism in exon 3 of DRD4
has been associated with TD. Although the exon 3
variable number tandem repeat was not associated
with TD, haplotypes consisting of four tag poly-
morphisms were associated with TD in males, sug-
gesting DRD4 may be involved in TD in the Cauca-
sian population [133].
Tyrosine hydroxylase (TH). Tyrosine hydroxylase
(EC 1.14.16.2) is involved in the conversion of
phenylalanine to dopamine. As the rate-limiting
enzyme in the synthesis of catecholamines, tyrosine
hydroxylase has a key role in the physiology of
adrenergic neurons. The TH variant rs6356 A/G has
been associated with SCZ [98].
Dystrobrevin binding protein 1 (DTNBP1) and
dysbindin. Dystrobrevin binding protein 1, a gene en-
coding dysbindin protein, is a susceptibility gene for
SCZ identified by family-based association analysis. A
large number of independent studies have reported evi-
dence for association between the dysbindin gene
(DTNBP1) and SCZ. Up to 14 SNPs spanning the
DTNBP1 locus may show association with SCZ in dif-
ferent studies [134]; however, a high-resolution melting

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 87
analysis (HRMA) to screen the 11 DTNBP1 exons with
their corresponding DNA variants in a sample from the
UK revealed no significant associations with SCZ [135].
DTNBP1 and MUTED encode proteins that belong to
the endosome-localized biogenesis of lysosome-related
organelles complex-1 (BLOC-1). BLOC-1 plays a key
role in endosomal trafficking and as such has been found
to regulate cell-surface abundance of the D2 dopamine
receptor, the biogenesis and fusion of synaptic vesicles,
and neurite outgrowth. These functions are pertinent to
both neurodevelopment and synaptic transmission, proc-
esses tightly regulated by selective cell-surface delivery
of membrane proteins to and from endosomes. It has
been proposed that cellular processes, such as endosomal
trafficking, act as convergence points in which multiple
small effects from polygenic genetic polymorphisms
accumulate to promote the development of SCZ [136].
BLOC-1 physically interacts with the adaptor protein
AP-3 complex, which is essential for vesicle or protein
sorting. Dysbindin forms a complex with the AP-3 com-
plex through the direct binding to its µ subunit. Dys-
bindin partially co-localized with the AP-3 complex in
CA1 and CA3 of mouse hippocampus, and at presynaptic
terminals and axonal growth cones of cultured hippo-
campal neurons. Suppression of dysbindin results in the
reduction of presynaptic protein expression and gluta-
mate release. Thus, dysbindin appears to participate in
the exocytosis or sorting of the synaptic vesicle via direct
interaction with the AP-3 complex [137]. Dysbindin is
involved in the exocytosis and/or formation of synaptic
vesicles. Proteins involved in protein localization process,
including Munc18-1, were identified as dysbindin-in-
teracting proteins [138]. A three-marker C-A-T dysbindin
haplotype is associated with increased risk for SCZ, de-
creased mRNA expression, reduced gray matter volume
in both the right dorsolateral prefrontal and left occipital
cortex, poorer cognitive performance, and early sensory
processing deficits [139]. 4 SNPs (rs3213207, rs1011313,
rs760761, and rs2619522) have been genotyped in a
large Korean SCZ sample. Haplotype analyses revealed a
significant association with SCZ with the haplotypes
A-C-C-C and A-C-T-A having an eminent protective
effect toward SCZ. The major contribution to the differ-
ence in the haplotype distribution between patients and
the controls was the rs760761 (C/T) and rs2619522 (A/C)
haplotypes. No association of DTNBP1 with other clini-
cal variables was found. This study suggests a possible
protective effect of rare DTNBP1 variants in SCZ [140].
Recent studies suggest a degree of overlap in genetic
susceptibility across the traditional categories of SCZ
and BD. DTNBP1 has also become a focus of investiga-
tion in BD. Seven DTNBP1 SNPs: rs2743852 (SNP C),
rs760761 (P1320), rs1011313 (P1325), rs3213207
(P1635), rs2619539 (P1655), rs16876571 and rs17470454,
were investigated using the SNPlex genotyping system.
Significant differences in genotypic and allelic frequen-
cies of rs3213207 and rs760761 of DTNBP1 were found
between bipolar patients and controls, as well as a global
haplotypic association and an association of a particular
haplotype with BD [141].
ErbB4 (v-Erb-a erythroblastic leukemia viral on-
cogene homolog 4 (avian)). ErbB4 is a growth factor
receptor tyrosine kinase essential for neurodevelopment.
Genetic variation in ErbB4 is associated with SCZ.
Risk-associated polymorphisms predict overexpression
of ErbB4 CYT-1 isoforms in the brain of schizophrenic
patients. The molecular mechanism of association is un-
clear because the polymorphisms flank exon 3 of the
gene and reside 700 kb distal to the CYT-1 defining exon.
Tan et al. [142] hypothesized that the polymorphisms are
indirectly associated with ErbB4 CYT-1 via splicing of
exon 3 on the CYT-1 background. They identified novel
splice isoforms of ErbB4, whereby exon 3 is skipped
(del.3). ErbB4 del.3 transcripts exist as CYT-2 isoforms
and are predicted to produce truncated proteins. Jux-
tamembrane (JM) splice variants of ErbB4, JM-a and
JM-b respectively, are characterized by the replacement
of a 75 nucleotide (nt) sequence with a 45-nt insertion,
and represent four alternative exons in the gene. Novel
splice variants of ErbB4 exist in the developing and adult
human brain and, given the failure to identify ErbB4 del3
CYT-1 transcripts, suggest that the association of risk
polymorphisms in the ErbB4 gene with CYT-1 transcript
levels is not mediated via an exon 3 splicing event, ac-
cording to Tan and coworkers [142].
Estrogen signaling. Estrogen signaling may be altered
in the brains of people with SCZ. DNA sequence varia-
tion in the estrogen receptor (ER) alpha gene (ESR1),
lower ERalpha mRNA levels, and/or blunted ERalpha
signaling is associated with SCZ. The naturally-occur-
ring truncated ERalpha isoform, Delta7, which acts as a
dominant negative, can attenuate gene expression in-
duced by the wild-type (WT) receptor in an estro-gen-
dependent manner in neuronal (SHSY5Y) and non-neu-
ronal (CHOK1 and HeLa) cells. ERalpha may also in-
teract with NRG1-ErbB4, a leading SCZ susceptibility
pathway. Reductions in the transcriptionally active form
of ErbB4 comprising the intracytoplasmic domain (ErbB4-
ICD) have been found in SCZ, and ERalpha and ErbB4
may converge to control gene expression. ErbB4-ICD
can potentiate the transcriptional activity of WT-ERalpha
at EREs in two cell lines and this potentiation effect is
abolished by the presence of Delta7-ERalpha. Conver-
gence between ERalpha and ErbB4-ICD in the transcrip-
tional control of ERalpha-target gene expression may
represent a convergent pathway that may be disrupted in
SCZ [143]. Studies in Japan reported no association be-
tween ERBB3 and SCZ in the Japanese population. Li et

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 88
al. [144] investigated the ERBB3 gene given the putative
functional nature of the gene and population heterogene-
ity between Asian and Caucasian. A Scottish case and
control samples were sequenced with four SNPs (rs705708
at intron 15, rs2271189, rs773123, rs2271188 at exon 27),
and association of rs773123, which is a nonsynonymous
Ser/Cys polymorphism located seven bases downstream
of rs2271189, with SCZ was detected in the Caucasian
population [144].
FADS2 (Fatty acid desaturase 2). Emerging evi-
dence suggests that SCZ might be associated with pe-
ripheral and central polyunsaturated fatty acid (PUFA)
deficits. Abnormalities in fatty acid composition have
been reported in peripheral tissues from drug-naïve first-
episode schizophrenic patients, including deficits in ω-3
and ω-6 PUFAs, which are partially normalized fol-
lowing chronic antipsychotic treatment. Post-mortem
cortical tissue from patients with SCZ also exhibits defi-
cits in cortical docosahexaenoic acid (DHA, 22:6n − 3)
and arachidonic acid (AA; 20:4n − 6) relative to normal
controls, and these deficits tend to be greater in drug-free
SCZ patients. Lower DHA (−20%) concentrations, and
significantly greater vaccenic acid (VA) (+12.5%) con-
centrations, were found in the orbitofrontal cortex (OFC)
(Brodmann’s area 10) of SCZ patients relative to normal
controls. Relative to age-matched same-gender controls,
OFC DHA deficits, and elevated AA:DHA, oleic
acid:DHA and docosapentaenoic acid (22:5n − 6):DHA
ratios, were found in male but not female SCZ patients.
SCZ patients that died of cardiovascular-related disease
exhibited lower DHA (−31%) and AA (−19%) concen-
trations, and greater OA (+20%) and VA (+17%) concen-
trations, relative to normal controls that also died of car-
diovascular-related disease. OFC DHA and AA deficits,
and elevations in oleic acid and vaccenic acid, were nu-
merically greater in drug-free SCZ patients and were
partially normalized in SCZ patients treated with anti-
psychotic medications (atypical > typical) [145]. Delta-5
desaturase (FADS1), delta-6 desaturase (FADS2), elon-
gase (HELO1 [ELOVL5]), peroxisomal (PEX19), and
delta-9 desaturase (stearoyl-CoA desaturase, SCD)
mRNA expression has been studied in the post-mortem
prefrontal cortex (PFC) of patients with SCZ. FADS2
mRNA expression was significantly greater in SCZ pa-
tients relative to controls (+36%), and there was a posi-
tive trend found for FADS1 (+26%). No differences were
found for HELO1 (+10%), PEX19 (+12%), or SCD
(−6%). Both male (+34%) and female (+42%) SCZ pa-
tients exhibited greater FADS2 mRNA expression rela-
tive to same-gender controls. Drug-free SCZ patients
(+37%), and SCZ patients treated with typical (+40%) or
atypical (+31%) antipsychotics, exhibited greater FADS2
mRNA expression relative to controls. Consistent with
increased delta6 desaturase activity, SCZ patients exhib-
ited a greater PUFA (product:precursor) 20:3/18:2 ratio
(+20%), and a positive trend was found for 20:4/18:2
(+13%). Abnormal elevations in delta-6 desaturase
(FADS2) expression in the PFC of SCZ patients are in-
dependent of gender and antipsychotic medications, and
might influence SCZ pathogenesis [146].
Fat mass- and obesity-associated gene (FTO).
Weight gain is one of the major adverse effects of anti-
psychotics. Pérez-Iglesias et al. [147] studied whether
the fat mass and obesity-associated gene (FTO) rs9939609
variant, the SNP that has shown the strongest association
with common obesity in different populations, and 3
other strong candidate genes involved in the leptin- sig-
naling pathway including leptin, leptin receptor, and Src
homology 2, influence weight gain during the first year
of antipsychotic treatment. Before antipsychotic treat-
ment, the homozygous subjects for the risk allele A of the
FTO rs9939609 variant had a higher body mass index at
baseline (24.2 T 3.8 kg/m2) than the AT/TT group (22.82
T 3.3 kg/m2); however, after 1 year of treatment with
antipsychotics, the magnitude of weight increase was
similar in the 3 genotypes defined by the rs9939609
variant. These results suggest that the pharmacological
intervention accompanied by changes in energy intake
and expenditure could suppress the genetic susceptibility
conferred by the FTO genotype, with no major impact of
other SNPs associated with weight gain.
FXYD6 (FXYD domain-containing ion transport
regulator 6). The FXYD6 gene is located in chromo-
some region 11q23.3, where previous studies have
shown an association with SCZ; but subsequent studies
failed to replicate this finding. Zhong et al. [148] inves-
tigated the relationship between FXYD6 locus and SCZ
in the Chinese population. Significant associations with
SCZ and the marker rs11544201 and the haplotype
rs10790212-rs11544201 were found, supporting that
FXYD6 might be a susceptibility gene of SCZ.
Fyn (FYN oncogene related to SRC, FGR, YES).
Fyn, a Src-family kinase, is highly expressed in brain
tissue and blood cells. FYN participates in brain devel-
opment, synaptic transmission through the phosphoryla-
tion of N-methyl-D-aspartate (NMDA) receptor subunits,
and the regulation of emotional behavior. Fyn is required
for the signal transduction in striatal neurons that is initi-
ated by haloperidol. FYN abnormalities are present in
patients with SCZ. A Western blot analysis revealed sig-
nificantly lower levels of Fyn protein among the patients
with SCZ and their relatives, compared with the level in
the control group. At the mRNA level, the splicing pat-
terns of FYN were altered in the patients and their rela-
tives; specifically, the ratio of fynDelta7, in which exon 7
is absent, was elevated. An expression study in HEK293T
cells revealed that FynDelta7 had a dominant-negative
effect on the phosphorylation of Fyn’s substrate. Down-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 89
regulation of Fyn protein or altered transcription of the
FYN gene might influence SCZ pathogenesis [149]. The
Src family tyrosine kinase FYN plays a key role in the
interaction between BDNF and glutamatergic receptor
N-methyl-D-aspartate. An association was found be-
tween FYN polymorphisms and cognitive test perform-
ance in schizophrenic patients. rs706895 (-93A/G in the
5’-flanking region), rs6916861 (Ex12 + 894T/G in the
3’-UTR) and rs3730353 (IVS10 + 37T/C in intron 10)
were investigated, and a significant association was
found between rs6916861 T/G and rs3730353 T/C poly-
morphisms of the FYN gene and BD [150].
GABAergic gene expression. Prefrontal deficits in
gamma-aminobutyric acid (GABA) and GABAergic
gene expression, including neuropeptide Y (NPY), soma-
tostatin (SST), and parvalbumin (PV) messenger RNAs
(mRNAs), have been reported for multiple SCZ cohorts.
Preclinical models suggest that a subset of these
GABAergic markers (NPY/SST) is regulated by BDNF,
which in turn is under the inhibitory influence of small
noncoding RNAs. Subjects with SCZ show deficits in
NPY and PV mRNAs. Within-pair differences in BDNF
protein levels exhibit strong positive correlations with
NPY and SST and a robust inverse association with
miR-195 levels, which in turn are not affected by anti-
psychotic treatment or genetic ablation of BDNF. Pre-
frontal deficits in a subset of GABAergic mRNAs, in-
cluding NPY, are dependent on the regional supply of
BDNF, which in turn is fine-tuned through a microRNA
(miRNA)-mediated mechanism [151].
Another important player in GABAergic neurotrans-
mission is the sodium-dependent and chloride-de-
pendent gamma-aminobutyric acid (GABA) trans-
porter 1 (SLC6A1), the target of a number of drugs of
clinical importance and a major determinant of synaptic
GABA concentrations. A novel 21 bp insertion in the
predicted promoter region of SLC6A1 was identified.
This mutation creates a second tandem copy of the se-
quence. Reporter assays showed that the insertion allele
significantly increases promoter activity in multiple cell
lines. The zinc finger transcription factor ZNF148 was
found to significantly transactivate the promoter and in-
crease expression when overexpressed but could not ac-
count for the differences in activity between the two al-
leles of the promoter. Copy number of the insertion se-
quence was associated with exponentially increasing
activity of a downstream promoter, suggesting that the
insertion sequence has enhanced activity when present in
multiple copies. The SLC6A1 promoter genotype was
found to predict SLC6A1 RNA expression in human
post-mortem hippocampal samples. The genotyping of
individuals from Tanzania suggested that the insertion
allele has its origin in Africa. This relatively common
polymorphism, of African origin, may prove useful in
predicting clinical response to pharmacological modula-
tors of SLC6A1 as well as GABAergic function in indi-
viduals of African descent [152].
Glutamatergic Neurotransmission
Glutamate cysteine ligase modifier (GCLM)
gene. Experimental evidence shows that glutathione
and its rate-limiting synthesizing enzyme, gluta-
mate-cysteine ligase (GCL), are involved in the
pathogenesis of SCZ. Genetic association was re-
ported between two SNPs lying in noncoding re-
gions of the glutamate cysteine ligase modifier
(GCLM) gene, which specifies for the modifier
subunit of GCL and SCZ. Ten sequence variations
were identified, five of which were not previously
described, but none of these DNA changes was
within the GCLM coding sequence, and in silico
analysis failed to indicate functional impairment
induced by these variations. It is unlikely that func-
tional mutations in the GCLM gene could play a
major role in genetic predisposition to SCZ [153].
Glutamate transporter genes. Glutamatergic neu-
rotransmission is involved in the pathogenesis of
schizophrenic psychosis, in particular regarding
cognitive and negative symptoms. The reported
molecular mechanisms include increased glutamate
transporter expression, and antipsychotic agents
such as clozapine were found able to suppress the
expression of these genes. The astroglial excita-
tory amino acid transporter genes EAAT1
(SLC1A3) and EAAT2 (SLC1A2) as well as the
neuronal transporter EAAT3 (SLC1A1) were
suppressed by aripiprazole, while the presynaptic
vesicular glutamate transporter vGluT1 (SLC17A7)
was transiently induced in hippocampal subregions
and EAAT4 (SLC1A6) was transiently suppressed
in frontocortical areas. These transcriptional effects
exerted by aripiprazole may counteract a glutama-
tergic deficit state and strengthen the neurotrans-
mission of glutamate with positive consequences on
cognitive and negative symptoms of SCZ [154].
Glutamic acid decarboxylase 2 and the gluta-
mine synthetase genes (GAD2, GLUL). Two
genes encoding glutamate metabolic enzymes, the
glutamic acid decarboxylase 2 gene (GAD2) and
the glutamine synthetase gene (GLUL) have been
studied in Japanese patients with SCZ, including 14
SNPs in GAD2 (approximately 91 kb in size) and 6
SNPs in GLUL (approximately 14 kb in size). No
significant “single-point” associations with the dis-
ease were found in any of the 20 SNPs after correc-
tion for multiple testing. Gene-gene interactions

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 90
with 6 glutamate receptor genes (GRIA4, GRIN2D,
GRIK3, GRIK4, GRIK5, GRM3) did not reveal
significant association, indicating that GAD2 and
GLUL do not play a major role in SCZ pathogene-
sis and that there is no gene-gene interaction be-
tween the eight genes in the Japanese population
[155]. The frequencies of GRIK3 (T928G) geno-
type distributions in patients with SCZ is similar to
those of their relatives. The frequency of the GG
genotype is significantly higher in patients than in
healthy controls. GG genotype distribution in rela-
tives is elevated compared with that in controls
[156].
Glutaminase (GLS1). Genetic knockdown of glu-
taminase (GLS1) to reduce glutamatergic transmis-
sion presynaptically by slowing the recycling of
glutamine to glutamate can produce a phenotype
relevant to SCZ. GLS1 heterozygous (GLS1 het)
mice showed about a 50% global reduction in glu-
taminase activity, and a modest reduction in gluta-
mate levels in brain regions relevant to SCZ patho-
physiology. GLS1 het mice were less sensitive to
the behavioral stimulating effects of amphetamine,
showed a reduction in amphetamine-induced striatal
dopamine release and in ketamine-induced frontal
cortical activation, suggesting that GLS1 het mice
are resistant to the effects of these pro-psychotic
challenges. GLS1 het mice showed clozapine-like
potentiation of latent inhibition, suggesting that re-
duction in glutaminase has antipsychotic-like prop-
erties. These observations suggest that presynaptic
modulation of the glutamine-glutamate pathway
through glutaminase inhibition may provide a new
direction for the pharmacotherapy of SCZ [157].
Glutamate receptor, ionotropic, delta 1 (GRID1).
Recent linkage and association data have implicated
the glutamate receptor delta 1 (GRID1) locus in the
etiology of SCZ. The distribution of CpG islands,
which are known to be relevant for transcriptional
regulation, was computationally determined at the
GRID1 locus, and the putative transcriptional regu-
latory region at the 5’-terminus was systematically
tagged using HapMap data. Genotype analyses
were performed with 22 haplotype-tagging SNPs
(htSNPs) and two SNPs in intron 2 and one in in-
tron 3 which have been found to be significantly
associated with SCZ. Association was obtained with
rs3814614, rs10749535, and rs11201985. Genetic
variants in the GRID1 transcriptional regulatory re-
gion may play a role in the etiology of SCZ [158].
Glutamate carboxypeptidase II (GCPII; FOLH1).
N-Acetyl aspartyl glutamate (NAAG) is an en-
dogenous agonist at the metabotropic glutamate re-
ceptor 3 (mGluR3, GRM3) receptor and antagonist
at the N-methyl D-aspartate (NMDA) receptor, both
receptors important to the pathophysiology of SCZ.
Glutamate carboxypeptidase II (GCPII), an enzyme
that metabolizes NAAG, is also implicated in psy-
chosis. In situ hybridization experiments to examine
expression of mGluR3 and GCPII transcripts along
the rostrocaudal axis of the human post-mortem
hippocampus show a significant reduction of GCPII
mRNA level in the anterior hippocampus in SCZ.
There is a positive correlation between GCPII and
mGluR3 mRNA in the CA3 of the control anterior
hippocampus which is not present in SCZ, probably
reflecting a disrupted functional interaction between
NAAG and mGluR3 in CA3 in SCZ [159].
Group III metabotropic glutamate receptor
genes, GRM4 and GRM7. Since a glutamatergic
dysfunction is involved in the pathophysiology of
SCZ, systematic studies on the association between
glutamate receptor genes and SCZ have been per-
formed in different populations. Shibata et al. [160]
reported association studies of SCZ with 8 and 43
common SNPs in group III metabotropic glutamate
receptor genes, GRM4 and GRM7, distributed in
the entire gene regions of GRM4 (>111 kb) and
GRM7 (>900 kb), respectively. Two neighboring
SNPs (rs12491620 and rs1450099) in GRM7
showed highly significant haplotype association
with SCZ. At least one susceptibility locus for SCZ
might be located within or nearby GRM7, whereas
GRM4 is unlikely to be a major susceptibility gene
for SCZ in the Japanese population [160].
Glycine-and serine-related genes. Differences in
the levels of the glutamate-related amino acids gly-
cine and serine in brain/plasma between schizo-
phrenic patients and normal subjects and changes in
the plasma concentrations of these amino acids ac-
cording to the clinical course have been reported.
Glycine and serine metabolism may be altered in
SCZ, and some genes related to the metabolism of
these amino acids have been suggested to be candi-
date genes for SCZ. Case-control genetic associa-
tion analysis of PHGDH, SHMT1, SRR, and DAO
was performed, showing no association with SCZ.
Only the two (rs3918347-rs4964770) and three
(rs3825251-rs3918347-rs4964770) SNP-based hap-
lotype analysis of the DAO gene showed an asso-
ciation with SCZ. None of the genotypes studied
was associated with changes in the plasma glycine
and L- and D-serine levels in SCZ [161].
NMDAR (N-Methyl D-aspartate (NMDA) re-
ceptor; GRIN1). Early postnatal inhibition of
NMDAR activity in corticolimbic GABAergic in-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 91
terneurons contributes to the pathophysiology of
SCZ-related disorders [162]. Consistent with the
NMDAR hypofunction theory of SCZ, in animal
models in which the essential NR1 subunit of the
NMDA receptor (NMDAR) was selectively elimi-
nated in 40% - 50% of cortical and hippocampal
interneurons in early postnatal development, dis-
tinct SCZ-related symptoms emerged after adoles-
cence, including novelty-induced hyperlocomotion,
mating and nest-building deficits, as well as anhe-
donia-like and anxiety-like behaviors. Social mem-
ory, spatial working memory and prepulse inhibi-
tion were also impaired. Reduced expression of
glutamic acid decarboxylase 67 and parvalbumin
was accompanied by disinhibition of cortical exci-
tatory neurons and reduced neuronal synchrony [162].
Phosphorylation of the NR1 subunit of NMDA re-
ceptors (NMDARs) at serine (S) 897 is markedly
reduced in SCZ patients. Knock-in mutations (mice
in which the NR1 S897 is replaced with alanine)
cause severe impairment in NMDAR synaptic in-
corporation and NMDAR-mediated synaptic trans-
mission. Phosphomutant animals have reduced
AMPA receptor (AMPAR)-mediated synaptic trans-
mission, decreased AMPARGluR1 subunit in the
synapse, impaired long-term potentiation, and be-
havioral deficits in social interaction and sensori-
motor gating, suggesting that an impairment in NR1
phosphorylation leads to glutamatergic hypofunc-
tion that can contribute to behavioral deficits asso-
ciated with psychiatric disorders [163].
Glutathione S-transferase GST-M1, GST-T1, and
GST-P1. Data from several studies suggest that oxidative
stress may play a role in the pathophysiology of tardive
dyskinesia (TD). Glutathione S-transferase (GST) en-
zymes exert a protecting effect on cells against oxidative
stress. The GST-M1, GST-T1, and GST-P1 loci were
analyzed in SCZ patients with TD and without TD. There
were no significant differences in the distributions of the
GST-M1, GST-T1, and GST-P1 genotypes between the
TD and non-TD groups. The Ile/Ile genotype of GST-P1
had higher AIMS score compared to Ile/Val + Val/Val
genotype, and MDR analysis did not show a significant
interaction between the three GST gene variants and
susceptibility to TD. These results suggest that GST gene
polymorphisms do not confer increased susceptibility to
TD in patients with SCZ but TD severity might be re-
lated with GST-P1 variants [164].
Glycogen synthase kinase-3 (GSK3). Adult neuro-
genesis augments neuronal plasticity, and deficient neu-
rogenesis might contribute to mood disorders and SCZ
and impede treatment responses. These diseases might be
associated with inadequately controlled glycogen syn-
thase kinase-3 (GSK3). There is a drastic 40% impair-
ment in neurogenesis in vivo in GSK3 alpha/beta (21A/
21A/9A/9A) knockin mice compared with wildtype mice.
Impaired neurogenesis could be due to effects of GSK3
in neural precursor cells (NPCs) or in surrounding cells
that modulate NPCs. In vitro proliferation was equivalent
for NPCs from GSK3 knockin and wild-type mice, sug-
gesting an in vivo deficiency in GSK3 knockin mice of
external support for NPC proliferation. Measurements of
two neurotrophins that promote neurogenesis demon-
strated less hippocampal vascular endothelial growth
factor but not BDNF in GSK3 knockin mice than wild-
type mice, reinforcing the possibility that insufficient
environmental support in GSK3 knockin mice might
contribute to impaired neurogenesis [165]. Accumulating
evidence implicates deregulation of GSK3ss as a con-
verging pathological event in AD and in neuropsychiatric
disorders, including BD and SCZ. These neurological
disorders share cognitive dysfunction as a hallmark. In
rodents, increased phosphorylation of GSK3ss at serine-9
has been reported following cognitive training in two
different hippocampus dependent cognitive tasks, i.e.
inhibitory avoidance and novel object recognition task.
Transgenic mice expressing the phosphorylation defec-
tive mutant GSK3ss [S9A] show impaired memory in
these tasks. GSK3ss [S9A] mice displayed impaired
hippocampal L-LTP and facilitated LTD. Application of
actinomycin, but not anisomycin, mimicked GSK3ss
[S9A]-induced defects in L-LTP, suggesting that tran-
scriptional activation is affected. This was further sup-
ported by decreased expression of the immediate early
gene c-Fos, a target gene of CREB. These data suggest a
role for GSK3ss in long-term memory formation, by in-
hibitory phosphorylation at serine-9 [166].
Golli-MBP. Multiple studies have reported oligoden-
drocyte and myelin abnormalities, as well as dysregula-
tion of their related genes, in brains of SCZ patients. One
of these genes is the myelin-basic-protein (MBP) gene,
which encodes two families of proteins: classic-MBPs
and golli-MBPs. While the classic-MBPs are predomi-
nantly located in the myelin sheaths of the nervous sys-
tem, the golli proteins are more widely expressed and are
found in both the immune and the nervous systems. As-
sociation between six (out of 26 genotyped) SNPs has
been found in Jewish Ashkenazi cohorts. Of these, three
(rs12458282, rs2008323, rs721286) are from one linkage
disequilibrium (LD) block which contains a CTCF bind-
ing region. Haplotype analysis revealed significant
“risk”/“protective” haplotypes for SCZ, suggesting that
golli-MBP is a possible susceptibility gene for SCZ
[167].
Growth factor signaling pathways. Evidence has
accumulated that the activity of the signaling cascades of
neuregulin-1, Wnt, TGF-beta, BDNF-p75 and DISC1 is
different between control subjects and patients with SCZ.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 92
These pathways are involved in embryonic and adult
neurogenesis and neuronal maturation. Clinical data in-
dicate that in SCZ the Wnt pathway is most likely hypo-
active, whereas the Nrg1-ErbB4, the TGF-beta- and the
BDNF-p75-pathways are hyperactive. Haplo-insuffiency
of the DISC1 gene is currently the best-established SCZ
risk factor. Preclinical experiments indicate that suppres-
sion of DISC1 signaling leads to accelerated dendrite
development in neuronal stem cells, accelerated migra-
tion and aberrant integration into the neuronal network.
Increasing NRG1-, BDNF- and TGF-beta signaling and
decreasing Wnt signaling also promotes adult neuronal
differentiation and migration. Deviations in these path-
ways detected in SCZ might contribute to premature
neuronal differentiation, accelerated migration and inap-
propriate insertion into the neuronal network. Neuronal
stem cells isolated from nasal biopsies from SCZ patients
display signs of accelerated development, whilst in-
creased erosion of telomeres and bone age provide fur-
ther support for accelerated cell maturation in SCZ [168].
The role of fibroblast growth factor receptors
(FGFR) in normal brain development has been well-
documented in transgenic and knock-out mouse models.
Changes in FGF and its receptors have also been ob-
served in SCZ and related developmental disorders. A
transgenic th(tk- )/th(tk-) mouse model with FGF receptor
signaling disruption targeted to dopamine (DA) neurons,
results in neurodevelopmental, anatomical, and bio-
chemical alterations similar to those observed in human
SCZ. In th(tk-)/th(tk-) mice hypoplastic development of
DA systems induces serotonergic hyperinnervation of
midbrain DA nuclei, demonstrating the co-developmen-
tal relationship between DA and 5-HT systems. Behav-
iorally, th(tk-)/th(tk-) mice displayed impaired sensory
gaiting and reduced social interactions correctable by
atypical antipsychotics and a specific 5-HT2A antagonist,
M100907. The adult onset of neurochemical and behav-
ioral deficits was consistent with the postpubertal time
course of psychotic symptoms in SCZ and related disor-
ders. The spectrum of abnormalities observed in
th(tk-)/th(tk-) mice and the ability of atypical neurolep-
tics to correct the behavioral deficits consistent with hu-
man psychosis suggests that midbrain 5-HT2A-control-
ling systems are important loci of therapeutic action
[169].
Heat shock proteins (HSPA1B). Pae et al. [170] in-
vestigated a group of SNPs of a set of genes coding for
heat shock proteins (HSPA1A, HSPA1B and HSPA1L)
and found a significant association between one HSPA1B
variation and SCZ. An association between a set of
variations (rs2227956, rs2075799, rs1043618, rs562047
and rs539689) within the same genes and a larger sample
of schizophrenic inpatients was studied. A single varia-
tion, rs539689 (HSPA1B), was found to be marginally
associated with Positive and Negative Syndrome Scale
(PANSS) positive scores at discharge, and haplotype
analysis revealed a significant association between im-
provement in PANSS scores with both A-C-G-G and
A-C-G-G haplotypes. These findings support a role of
heat shock proteins in the pathophysiology of SZ [170].
HOMER2. SNPs rs2306428 and rs17158184 of
HOMER2 were significantly associated with SCZ in Irish
samples. The protective allele at rs2306428 removes a
predicted splice-enhancer binding site where HOMER2
is naturally truncated. No allelic effect of rs2306428 on
neuropsychological function or on HOMER2 splicing was
found [171].
IFNG (Interferon gamma). Dysregulation of the cy-
tokine network in schizophrenia has been well docu-
mented. Such changes may occur due to disturbances in
cytokine levels that are linked to polymorphisms of cy-
tokine genes. Paul-Samojedny et al. [172] performed the
first study to examine the association between the IFN-γ
gene polymorphism and psychopathological symptoms
in Polish patients with paranoid SCZ. A SNP in the IFN-γ
gene (+874T/A, rs 62559044) was found to be associated
with paranoid SCZ in males, but not in females. The
presence of allele A at position +874 in the IFN-γ gene
correlates with 1.66-fold higher risk of paranoid SCZ
development in males.
3’ Ig heavy chain locus enhancer HS1,2*A (IGHA1).
Infectious and autoimmune pathogenic hypotheses of
SCZ have been proposed, prompting searches for anti-
bodies against viruses or brain structures, and for altered
levels of immunoglobulins. Allele frequencies of the Ig
heavy chain 3’ enhancer HS1,2*A are associated with
several autoimmune diseases, suggesting a possible cor-
relation between HS1,2 alleles and Ig production. Levels
of serum Igs and HS1,2*A genotypes have been studied
in SCZ. Serum concentrations of Ig classes and IgG sub-
classes are higher in SCZ (80%) as compared to controls
(68%). An increased frequency of the HS1,2*2A allele
corresponded to increased Ig plasma levels, while an
increased frequency of the HS1,2*1A allele corre-
sponded to decreased Ig plasma levels. The transcription
factor SP1 bound to the polymorphic region of both
HS1,2*1A and HS1,2*2A while NF-kB bound only to
the HS1,2*2A. Differences in transcription factor bind-
ing sites in the two allelic variants of the 3’ IgH enhancer
HS1,2 may provide a mechanism by which differences in
Ig expression are affected [173].
Insulin-degrading enzyme (IDE). Insulin-degrading
enzyme (IDE) is a neutral thiol metalloprotease, which
cleaves insulin with high specificity. IDE also hydrolyzes
Aβ, glucagon, IGF I and II, and beta-endorphin. The
gene encoding IDE is located on chromosome 10q23-q25,
a gene locus linked to SCZ. Insulin resistance with brain
insulin receptor deficits/receptor dysfunction was re-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 93
ported in SCZ. IDE cleaves IGF-I and IGF-II, which are
implicated in the pathophysiology of SCZ, although po-
lymorphic CA repeat in IGF1 did not show association
with SCZ [174]. Brain gamma-endorphin levels, liber-
ated from beta-endorphin exclusively by IDE, have been
reported to be altered in SCZ. Studies on the expression
of IDE protein in post-mortem brains of patients with
SCZ and controls revealed a reduced number of IDE-ex-
pressing neurons and IDE protein content in the left and
right dorsolateral prefrontal cortex in SCZ compared
with controls, but not in other brain areas. Haloperidol
might exert some effect on IDE, through changes of the
expression levels of its substrates IGF-I and II, insulin
and beta-endorphin. Reduced cortical IDE expression
might be part of the disturbed insulin signaling cascades
found in SCZ and it might contribute to the altered me-
tabolism of certain neuropeptides (IGF-I and IGF-II,
beta-endorphin) in SCZ [175].
Interleukins. SCZ has been associated with abnor-
malities in cytokines and cytokine receptors potentially
linked to a defective immunological function in psy-
chotic disorders. Some reports have shown that IL-3,
colony stimulating factor 2 receptor alpha (CSF2RA)
and IL-3 receptor alpha (IL3RA) are associated with
SCZ. A significant association for IL3RA-rs6603272, but
not for rs6645249, and a genotypic association of both
polymorphisms with SCZ was found in a Chinese popu-
lation. Haplotype TDT was statistically significant, with
the rs6603272 (T) - rs6645249 (G) haplotype signifi-
cantly associated with SCZ [176]. Interleukin-10
(IL-10), an important immunoregulatory cytokine, is
located on chromosome 1q31-32, a region previously
reported to be linked to SCZ in genetic studies. Poly-
morphisms at positions −1082, −819 and −592 in the
IL-10 promoter region were determined in Turkish SCZ
patients, and significant differences were observed in
both allelic and genotypic frequencies of the -592A/C
polymorphism. GTA homozygotes (the high IL-10-pro-
ducing haplotype) were more prevalent among schizo-
phrenic patients than in controls, suggesting that the
IL-10 gene promoter polymorphism may be one of the
susceptibility factors to develop SCZ in the Turkish
population [177].
ITIH3/4 (Inter-alpha-tryptin inhibitor, heavy chain
4), CACNA1C (Calcium channel, voltage-dependent,
L type, alpha-1C subunit), and SDCCAG8 (Serologi-
cally defined colon cancer antigen 8). The Schizophre-
nia Psychiatric Genome-Wide Association Study Con-
sortium (PGC) highlighted 81 single-nucleotide poly-
morphisms (SNPs) with moderate evidence for associa-
tion to schizophrenia. After follow-up in independent
samples, seven loci attained genome-wide significance
(GWS), but multi-locus tests suggested some SNPs that
did not do so represented true associations. Hamshere et
al. [47] found that variants at three loci (ITIH3/4,
CACNA1C and SDCCAG8) are associated with SCZ.
JARID2 (Jumonji (JMJ), at-rich interactive do-
main 2). An association was found of D6S289, a dinu-
cleotide repeat polymorphism in the JARID2 gene, with
SCZ and was confirmed by individual genotyping after a
genome screen with 400 microsatellite markers spaced at
approximately 10 cM in two DNA pools consisting of
119 SCZ patients and 119 controls recruited from a ho-
mogenous population in the Chang Le area of the Shan-
dong peninsula of China. rs2235258 and rs9654600 in
JARID2 showed association in allelic, genotypic and
haplotypic tests with SCZ patients [178].
KCNH2 (Potassium voltage-gated channel, sub-
family h (eag-related), member 2). Organized neuronal
firing is crucial for cortical processing and this is dis-
rupted in SCZ. A primate-specific isoform (3.1) of the
ether-a-go-go-related K+ channel KCNH2 that modulates
neuronal firing has been identified. KCNH2-3.1 messen-
ger RNA levels are comparable to full-length KCNH2-
1A levels in brain but three orders of magnitude lower in
heart. In hippocampus from individuals with SCZ,
KCNH2-3.1 expression is 2.5-fold greater than KCNH2-
1A expression. A meta-analysis of five clinical data sets
shows association of SNPs in KCNH2 with SCZ.
Risk-associated alleles predict lower intelligence quo-
tient scores and speed of cognitive processing, altered
memory-linked functional magnetic resonance imaging
signals and increased KCNH2-3.1 mRNA levels in
post-mortem hippocampus. KCNH2-3.1 lacks a domain
that is crucial for slow channel deactivation. Overexpres-
sion of KCNH2-3.1 in primary cortical neurons induces a
rapidly deactivating K+ current and a high-frequency,
nonadapting firing pattern [179].
The potassium channels are thought to have a role in
modulating electrical excitability in neurons, regulating
calcium signaling in oligodendrocytes and regulating
action potential duration in presynaptic terminals and
GABA release. Shen et al. [180] chose three potassium
channel genes, KCNH1, KCNJ10 and KCNN3, to inves-
tigate the role of potassium channels in SCZ by geno-
typing 23 SNPs (9 in KCNH1, 5 in KCNJ10 and 9 in
KCNN3) in a Han Chinese sample consisting of 893
SCZ patients and 611 healthy controls. No significant
difference in allelic or genotypic frequency was revealed
between SCZ patients and healthy individuals. According
to these results, it appears that the 23 SNPs within the
three potassium genes examined by Shen et al. do not
play a major role in SCZ in the Han Chinese population.
Kynurenine pathway. Some studies of mRNA ex-
pression, protein expression, and pathway metabolite
levels have implicated dysregulation of the kynurenine
pathway in the etiology of SCZ and BD. A SNP in each
of six genes, TDO2 (tryptophan 2,3-dioxygenase),

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 94
HM74 (chemokine receptor HM74/ G protein-coupled
receptor 109B; GRP109B), HM74A (G protein-cou-
pled receptor 109A; GRP109A), MCHR1 (melanin-
concentrating hormone receptor 1/G protein-coupled
receptor 24; GPR24), MCHR2 (melanin-concentrat-
ing hormone receptor 2), and MC5R (melanocortin 5
receptor), was tested for association with SCZ. An A
allele in HM74 was significantly associated with SCZ
and with SCZ plus BD combined. Augmentation of dis-
ease risk was found for the complex genotype HM74[A,
any] + MCHR1[T, any] + MCHR2[C, any] which con-
ferred an OR maximal for the combined diagnostic cate-
gory of SCZ plus BD, carried by 30% of the cases.
TDO2[CC] + MC5R[G, any] + MCHR2[GC] conferred
an OR maximal for SCZ alone, carried by 8% of SCZ
cases. The combined risk posed by these related, com-
plex genotypes is greater than any identified single locus
and may derive from co-regulation of the kynurenine
pathway by interacting genes, a lack of adequate mela-
notropin-controlled sequestration of the kynurenine-de-
rived pigments, or the production of melanotropin re-
ceptor ligands through kynurenine metabolism [181].
MAGI2 (Membrane-associated guanylate kinase,
WW and PDZ domains-containing, 2). MAGI2, a large
gene (∼1.5 Mbps) that maps to chromosome 7q21, is
involved in recruitment of neurotransmitter receptors
such as AMPA- and NMDA-type glutamate receptors.
Koide et al. [182] examined the relationship of SNP
variations in MAGI2 and risk for SCZ in a large Japa-
nese sample and explored the potential relationships be-
tween variations in MAGI2 and aspects of human cogni-
tive function related to glutamate activity. They found
suggestive evidence for genetic association of common
SNPs within MAGI2 locus and SCZ.
Major histocompatibility complex (MHC). The In-
ternational Schizophrenia Consortium [183] and the
European SGENE-plus [184] found significant associa-
tion with several markers spanning the major histocom-
patibility complex (MHC) region on chromosome 6p21.3-
22.1. In the MHC region, the five genome-wide signifi-
cant markers (MHC/HIST1H2BJ: rs6913660-C; MHC/
PRSS16: rs13219354-T; MHC/PRSS16: rs6932590-T;
MHC/PGBD1: rs13211507-T; MHC/NOTCH4: rs3131296-
G) have risk alleles with average control frequencies
between 78% and 92%. The five chromosome 6p mark-
ers, spanning about 5 Mb, cover 1.4 cM and exhibit sub-
stantial linkage disequilibrium. rs3131296 shows corre-
lation with classical HLA alleles (HLA-A*0101, HLA-
B*0801, HLA-C*0701, HLA-DRB*0301, HLA-DQA*
0501, HLA-DQB*0201) [183,184]. This finding might
give support to the infective-neuroimmune hypothesis of
SCZ. Bergen et al. [48] reported a genome-wide signify-
cant association in the MHC region (rs886424). Single-
ton deletions were more frequent in both case groups
compared with controls, whereas the largest CNVs (>500
kb) were significantly enriched only in SCZ cases. Two
CNVs (16p11.2 duplications and 22q11 deletions) asso-
ciated with SCZ were also overrepresented in the SCZ
sample.
Malic enzyme 2. Some studies have identified a puta-
tive gene locus for both SCZ and BD in the chromosome
18q21 region. Microsatellite analyses showed evidence
of association at two contiguous markers, both located at
the same genetic distance and spanning approximately 11
known genes. In a corollary gene expression study, one
of these genes, malic enzyme 2 (ME2), showed levels of
gene expression 5.6-fold lower in anterior cingulate tis-
sue from post-mortem bipolar brains. Subsequent analy-
sis of individual SNPs in strong linkage disequilibrium
with the ME2 gene revealed one SNP and one haplotype
associated with the phenotype of psychosis. ME2 inter-
acts directly with the malate shuttle system, which has
been shown to be altered in SCZ and BD, and has roles
in neuronal synthesis of glutamate and gamma-amino
butyric acid. Genetic variation in or near the ME2 gene
might be associated with both psychotic and manic dis-
orders, including SCZ and BD [185].
Matrix metaloproteinases. Recent studies have de-
monstrated that matrix metalloproteinase 3 (MMP3) is a
key event in associative memory formation, learning and
synaptic plasticity, which are important in psychiatric
disorders. Genetic variations in the MMP3 -1171 5A/6A
have been studied in patients with SCZ. The frequencies
of the 6A6A genotype and 6A allele distributions of
MMP3 in patients with SCZ were significantly decreased
when compared with controls. In contrast, in patients
with SCZ, the distribution of the 5A5A genotype and 5A
allele were significantly increased as compared with
healthy controls. When the frequencies of genotypes or
alleles in schizophrenic patients and bipolar patients
were compared, 6A6A genotype and 6A allele in patients
with BD-I were significantly higher than in patients with
SCZ. A potential link between MMP3-1171 5A/6A vari-
ants and SCZ might be possible [186].
Matrix metallopeptidase 9 (gelatinase B, 92 kDa
gelatinase, 92 kDa type IV collagenase) (MMP9). This
gene plays a role in many pathological conditions such as
cancer and heart disease and brain functions. It has been
hypothesized that the MMP-9 gene may be associated
with bipolar mood disorder. A functional −1562C/T
polymorphism of the MMP-9 gene was genotyped. Pa-
tients with bipolar mood disorder had significant pre-
ponderance of T allele vs C allele of 1562C/T poly-
morphism of the MMP-9 gene, compared to healthy con-
trol subjects. The higher frequency of T allele com-
pared to healthy subjects was especially evident in a
subgroup of patients with BD, type II. The results may
provide the first evidence for an involvement of the

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 95
MMP-9 gene in the pathogenesis of bipolar mood disor-
der. They may also contribute to explaining genetic con-
nection between bipolar mood disorder and some so-
matic illnesses. MMP-9 may be a common susceptibility
gene to major psychoses with different allelic variants
occurring in bipolar illness and SCZ [187].
MCTP2 (Multiple C2 domains, transmembrane 2).
The MCTP2 gene is involved in intercellular signal
transduction and synapse function. Djurovic et al. [188]
genotyped 37 tagging SNPs across the MCTP2 gene to
study a possible association with SCZ in three inde-
pendent Scandinavian samples, and found a possible
involvement of MCTP2 as a potential novel susceptibil-
ity gene for SCZ.
Methylenetetrahydrofolate reductase (MTHFR).
The frequency of homozygosity for the 677T allele of the
MTHFR gene was found higher in Chinese patients with
SCZ than in controls. A significant difference was ob-
served in the plasma homocysteine levels among the
different genotypes in the patient and control groups.
Both elevated plasma homocysteine levels and variation
in the MTHFR 677C > T gene are related to increased
rates of SCZ and are risk factors for psychosis [189]. The
methylenetetrahydrofolate reductase gene (MTHFR)
functional polymorphism A1298C may be a risk factor
for schizophrenia. Zhang et al. [190] found a genetic
association between the MTHFR A1298C polymorphism
and SCZ in the Chinese Han population.
MDGA1 (MAM domain-containing glycosylphos-
phatidylinositol anchor 1; glycosylphosphatidylinosi-
tol-MAM; GPIM). The structural, cytoarchitectural and
functional brain abnormalities reported in patients with
mental disorders may be due to aberrant neuronal migra-
tion influenced by cell adhesion molecules. MDGA1,
like Ig-containing cell adhesion molecules, has several
cell adhesion molecule-like domains. Kahler et al. [191]
reported that the MDGA1 gene was a SCZ susceptibility
gene in the Scandinavian population. Li et al. [192] in-
vestigated the association of MDGA1 with SCZ in the
Chinese Han population and found that the genotype
frequency of rs11759115 differed significantly between
patients and controls. The C-C haplotype of rs11759115-
rs7769372 was also positively associated with SCZ.
rs1883901 was found to be positively associated with
bipolar disorder, and the A-G-G haplotype of rs1883901-
rs10807187 - rs9462343 was also positively associated
with bipolar disorder.
NADPH oxidase NOX2. Sorce et al. [193] investi-
gated the role of NOX2 in acute responses to subanes-
thetic doses of ketamine. In wild-type mice, ketamine
caused rapid behavioral alterations, release of neuro-
transmitters, and brain oxidative stress, whereas NOX2-
deficient mice did not display such alterations. De-
creased expression of the subunit 2A of the NMDA re-
ceptor after repetitive ketamine exposure was also pre-
cluded by NOX2 deficiency. Neurotransmitter release
and behavioral changes in response to amphetamine were
not altered in NOX2-deficient mice. NOX2 is a major
source of ROS production in the prefrontal cortex con-
trolling glutamate release and associated behavioral al-
terations after acute ketamine exposure. Prolonged NOX2-
dependent glutamate release may lead to neuroadaptative
downregulation of NMDA receptor subunits. Subanes-
thetic doses of NMDA receptor antagonist ketamine in-
duce schizophrenia-like symptoms in humans and be-
havioral changes in rodents. Subchronic administration
of ketamine leads to loss of parvalbumin-positive in-
terneurons through reactive oxygen species (ROS), gen-
erated by the NADPH oxidase NOX2. However, keta-
mine induces very rapid alterations, in both mice and
humans.
NALCN (Sodium leak channel, nonselective). Teo et
al. [22] screened markers for nominal significance and
for statistical significance after multiple-testing correc-
tion in treatment-resistant schizophrenia and found that
the most significant single nucleotide polymorphism was
the rs2152324 marker in the NALCN gene (13q33.1).
Neural cell adhesion molecule 1 (NCAM1). Neural
cell adhesion molecule 1 (NCAM1) is involved in sev-
eral neurodevelopmental processes and abnormal ex-
pression of this gene has been associated in the pathol-
ogy of SCZ and, thus, altered NCAM1 expression may
be characteristic of the early stages of the illness. NCAM
is a membrane-bound cell recognition molecule that ex-
erts important functions in normal neurodevelopment
including cell migration, neurite outgrowth, axon fas-
ciculation, and synaptic plasticity. Alternative splicing of
NCAM mRNA generates three main protein isoforms:
NCAM-180, −140, and −120. Ectodomain shedding of
NCAM isoforms can produce an extracellular 105 - 115
kDa soluble neural cell adhesion molecule fragment
(NCAM-EC) and a smaller intracellular cytoplasmic
fragment (NCAM-IC). NCAM also undergoes a unique
post-translational modification in brain by the addition of
polysialic acid (PSA)-NCAM. Both PSA-NCAM and
NCAM-EC have been implicated in the pathophysiology
of SCZ. mRNA expression of one of these isoforms, the
180 kDa isoform of NCAM1 (NCAM-180), was studied
in the Brodmann Area (BA) 46, BA10 and BA17, of
post-mortem samples from patients with SCZ. NCAM-
180 mRNA expression was increased in BA46 from sub-
jects with SCZ compared to controls. No differences in
the expression of NCAM-180 mRNA were observed in
BA10 or BA17. NCAM-180 mRNA expression is altered
in a regionally-specific manner in early stages of SCZ
[194]. The developmental expression patterns of the
main NCAM isoforms and PSA-NCAM have been de-
scribed in rodent brain and across human cortical devel-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 96
opment. Each NCAM isoform (NCAM-180, −140, and
−120), post-translational modification (PSA-NCAM) and
cleavage fragment (NCAM-EC and NCAM-IC) shows
developmental regulation in frontal cortex. NCAM-180,
−140, and −120, as well as PSA-NCAM, and NCAM-IC
all showed strong developmental regulation during fetal
and early postnatal ages, consistent with their identified
roles in axon growth and plasticity. NCAM-EC demon-
strated a more gradual increase from the early postnatal
period to reach a plateau by early adolescence, potentially
implicating involvement in later developmental processes.
Altered NCAM signaling during specific developmental
intervals might affect synaptic connectivity and circuit
formation, and thereby contribute to neurodevelopmental
disorders [195].
Neuregulin (NRG1, NRG3). Chromosome 8p12 has
been identified as a locus for SCZ in several genome-
wide scans and confirmed by meta-analysis of published
linkage data. Systematic fine mapping using extended
Icelandic pedigrees identified an associated haplotype in
the gene neuregulin 1 (NRG1), also known as heuregulin,
glial growth factor, NDF43 and ARIA. A 290 kb core at
risk haplotype at the 5’ end of the gene (HAPICE), de-
fined by five SNPs and two microsatellite polymor-
phisms, was found to be associated with SCZ in the Ice-
landic and Scottish populations. Analysis of the HAPICE
markers showed the association of a 7-marker and
2-microsatellite haplotype, different from the haplotypes
associated in the Icelandic population, and overrepre-
sented in northern Swedish control individuals. Signifi-
cant association was found with 5 SNPs located in the
second intron of NRG1. Furthermore, 2-, 3-, and 4-SNP
windows that comprise these SNPs were also associated.
One protective haplotype (0% vs 1.8%) and 1 disease
risk-causing haplotype (40.4% vs 34.9%) were defined
[196]. Li et al. [197] analyzed data from the SNP mark-
ers SNP8NRG241930, SNP8NRG243177, SNP8NRG-
221132 and SNP8NRG221533, and the microsatellite
markers 478B14-848, 420M9-1395. Across these studies,
a strong positive association was found for all six poly-
morphisms. The haplotype analysis also showed signifi-
cant association in the pooled international populations.
In Asian populations, the risk haplotype was focused
around the two microsatellite markers, 478B14-848,
420M9-1395 (haplotype block B), and in Caucasian
populations with the remaining four SNP markers (hap-
lotype block A). This meta-analysis supports the in-
volvement of NRG1 in the pathogenesis of SCZ, but
with association between two different but adjacent hap-
lotype blocks in the Caucasian and Asian populations
[197]. The promoter for the NRG1 isoform, SMDF, maps
to the 3’ end of the gene complex. Analysis of the SNP
data-base revealed several polymorphisms within the ap-
proximate borders of the region immunoprecipitated in
ChIP-chip experiments, one of which is rs7825588. This
SNP was analyzed in patients with SCZ and BD and its
effect on promoter function was assessed by electromo-
bility gel shift assays and luciferase reporter constructs.
A significant increase in homozygosity for the minor
allele was found in patients with SCZ, but not in BD.
Molecular studies demonstrated modest, but statistically
significant, allele-specific differences in protein binding
and promoter function. The findings suggest that homo-
zygosity for rs725588 could be a risk genotype for SCZ
[198]. Prata et al. [199] tested 4 SNPs, SNP8NRG221533
(rs35753505), SNP8NRG241930, SNP8NRG243177
(rs6994992) and SNPNRG222662 (rs4623364) for allelic
and haplotypic association with BD and the presence of
psychotic or mood-incongruent psychotic features. No-
minal allele-wise significant association for SNP8NRG-
221533 was found, with the T allele being overrepresent-
ed in SCZ. This is the opposite allelic association to the
original association study where the C allele was associ-
ated with SCZ. Subphenotypes were significantly associ-
ated with the SNP8NRG221533(T)-SNP8NRG241930-
(G) haplotype and with the SNP8NRG221533 (T)-SNP8-
NRG222662-(C)-SNP8NRG241930(G) haplotype in the
case of the broader subphenotype of psychotic bipolar.
This study supports the hypothesis that NRG1 may play
a role in the development of BD, especially in psychotic
subtypes, albeit with different alleles to previous associa-
tion reports in SCZ and BD [199]. NRG1 influences the
development of white matter connectivity. The cingulum
bundle is a white matter structure implicated in SCZ.
Abnormalities in the structural integrity of the anterior
cingulum in patients with SCZ have been reported. Frac-
tional anisotropy is reduced in the anterior cingulum in
SCZ. There is interaction between genetic variation in
NRG1 and diagnosis of SCZ, and patients with the T
allele for SNP8NRG221533: rs35753505 have decreased
anterior cingulum fractional anisotropy compared with
patients homozygous for the C allele and healthy con-
trols who were T-carriers [200]. NRG1 is one of the most
researched genes associated with SCZ. Although three
meta-analyses in this area have been published, the re-
sults have been inconclusive and even conflicting. Gong
et al. [201] performed a meta-analysis of 26 published
case-control and family-based association studies up to
September 2008 covering 8049 cases, 8869 controls and
1515 families. Across these studies, the conclusions are
as follows: 1) only SNP8NRG- 221132, 420M9-1395(0)
and 478B14-848(0) showed significant association in the
relatively small sample size; 2) the association analysis
of case-control studies was statistically consistent with
that of family studies; and 3) the matrix of coancestry
coefficient suggested obvious population stratification.
The study reveals that one SNP of the NRG1 gene does
not contribute significantly to SCZ and that population

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 97
stratification is evident [201]. Quantitative real-time PCR
was used to check the genotypes of four SNPs- rs221533
(C/T), rs7820838 (C/T), 433E1006 (A/G) and rs3924999
(C/T), located at the 510 terminus of the NRG1 gene, in
258 Chinese Han schizophrenic parent-proband trios.
There was significant transmission disequilibrium in
allelic transmission of C, A, T from rs221533, 433E1006,
rs3924999 loci, respectively. Haplotype was analyzed at
a frequency exceeding 1%. In three-marker-haplotype,
C/C/G and C/C/A (rs221533, rs7820838, 433E1006)
transmitted predominantly. In four-marker-haplotype
(rs221533, rs7820838, 433E1006, rs3924999), C/C/G/T,
C/C/A/C and C/C/A/T showed transmission disequilib-
rium. According to these studies, the NRG1 gene poly-
morphism is significantly associated with SCZ in Chi-
nese Han, especially in the positive subtype of SCZ
[202].
NRG1 is a pleiotropic growth factor involved in di-
verse aspects of brain development and function. In SCZ,
expression of the NRG1 type I isoform is selectively
increased [203]. NRG1 and ERBB4 have emerged as
some of the most reproducible SCZ risk genes. The
Neuregulin (NRG)/ErbB4 signaling pathway has been
implicated in dendritic spine morphogenesis, glutamater-
gic synaptic plasticity, and neural network control.
ErbB4-expressing interneurons, but not pyramidal neu-
rons, are primary targets of NRG signaling in the hippo-
campus and implicate ErbB4 as a selective marker for
glutamatergic synapses on inhibitory interneurons [204].
Structural brain abnormalities are present at early
phases of psychosis and might be the consequence of
neurodevelopmental derailment. The SNP8NRG243177
risk T allele was significantly associated, in an allele
copy number-dependent fashion, with increased lateral
ventricle volume in psychosis. Genotype explained 7%
of the variance of lateral ventricle volume. Genetic va-
riations of the NRG1 gene can contribute to the enlar-
gement of the lateral ventricles described in early phases
of SCZ [205].
Linkage studies have implicated 10q22-q23 as a SCZ
susceptibility locus in Ashkenazi Jewish (AJ) and Han
Chinese from Taiwan populations. Chen et al. [206] per-
formed a peakwide association fine mapping study by
using 1414 SNPs across approximately 12.5 Mb in
10q22-q23 of Ashkenazi Jews, and found strong evi-
dence of association by using the “delusion” factor as the
quantitative trait at three SNPs (rs10883866, rs10748842,
and rs6584400) located in a 13 kb interval in intron 1 of
NRG3. NRG3 is primarily expressed in the CNS and is
one of three paralogs of NRG1 [206]. Zhang et al. [207]
genotyped 13 SNPs within NRG3 to investigate the as-
sociation between NRG3 and schizophrenia in 488 pa-
tients and 506 compared controls in Northwest China
and no association was detected either in SNPs or in
haplotypes.
Neurogranin (NRGN). A marker located 3457 bases
upstream of the neurogranin gene (NRGN) on 11q24
(rs128078009-T) has been associated with SCZ [208].
This marker has an average risk allele control frequency
of 83%. Another NRGN SNP (rs7113041) has been re-
ported to be associated with SCZ in Portuguese patients
[209]. NRGN is expressed exclusively in brain under
control of thyroid hormones, and is reduced in the pre-
frontal cortex of patients with SCZ. NRGN encodes a
postsynaptic protein kinase substrate that binds calmo-
dulin in the absence of calcium. NRGN is abundant in
dendritic spines of hippocampal CA1 pyramidal neurons,
probably acting as a calmodulin reservoir. Altered
NRGN activity might mediate the effects of NMDA hy-
pofunction implicated in SCZ pathogenesis [208].
Neuropeptide Y. It has been suggested that hypoac-
tivity of neuropeptide Y (NPY) may be involved in the
pathophysiology of SCZ. A post-mo rtem study revealed a
decreased level of NPY in the brain of patients with SCZ.
An increased level of NPY after antipsychotic treatment
was also reported in animal brain and cerebrospinal fluid
of patients. A positive association between the functional
−485C > T polymorphism in the NPY gene and SCZ was
reported in the Japanese population; however, more re-
cent studies suggest that the NPY −485C > T polymor-
phism may not confer susceptibility to SCZ [210].
Neurotrophin receptor (NTRK-3). Based on the
important role of neurotrophic factors in brain develop-
ment and plasticity as well as their extensive expression
in hippocampal areas, it has been hypothesized that a
variation in the neurotrophin receptor 3 gene (NTRK-3)
is associated with hippocampal function and SCZ.
rs999905 was significantly associated with SCZ and the
haplotype block that includes markers rs999905 and
rs4887348 remained significant after permutation tests.
The NTRK-3 gene influences hippocampal function and
may modify the risk for SCZ [211].
Nitric oxide synthase (NOS). The neuronal nitric ox-
ide synthase gene (NOS1) is located on 12q24.2-q24.31,
in a susceptibility region for SCZ, and produces nitric
oxide (NO) in the brain. NO plays a role in neurotrans-
mitter release and is the second messenger of the
N-methyl-D-aspartate (NMDA) receptor. It is also con-
nected to the dopaminergic and serotonergic neural
transmission systems. Therefore, abnormalities in the NO
pathway are thought to be involved in the pathophysiol-
ogy of SCZ. NOS1-G/G is associated with clinically sig-
nificant variation in cognition. Whether this is a mecha-
nism by which SCZ risk is increased is yet to be con-
firmed [212]. Several genetic studies showed an associa-
tion of NOS1 with SCZ; however, results of replication
studies have been inconsistent. In a replication study of
NOS1 with SCZ in a Japanese sample, Okumura et al.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 98
[213] selected seven SNPs (rs41279104, rs3782221,
rs3782219, rs561712, rs3782206, rs2682826, and
rs6490121) in NOS1 that were positively associated with
SCZ in previous studies. Two SNPs showed an associa-
tion with Japanese schizophrenic patients (rs3782219,
rs3782206); however, these associations might have re-
sulted from type I error on account of multiple testing
[213]. In other studies no evidence was found of associa-
tion with rs6490121 in NOS1 [214].
Association between markers within a region on
chromosome 1q23.3, including the NOS1AP (nitric ox-
ide synthese 1 (neuronal) adaptor protein) gene and
SCZ has been found in a set of Canadian families of
European descent, as well as significantly increased ex-
pression in SCZ of NOS1AP in unrelated post-mortem
samples from the dorsolateral prefrontal cortex. Using
the posterior probability of linkage disequilibrium
(PPLD) to measure the probability that a SNP is in link-
age disequilibrium with SCZ, Wratten et al. [215] evalu-
ated 60 SNPs from NOS1AP in 24 Canadian families
demonstrating linkage and association to this region.
Two human neural cell lines (SK-N-MC and PFSK-1)
were transfected with a vector containing each allelic
variant of the NOS1AP promoter and a luciferase gene.
Three SNPs produced PPLDs > 40%. One of them,
rs12742393, demonstrated significant allelic expression
differences in both cell lines tested. The allelic variation
at this SNP altered the affinity of nuclear protein binding
to this region of DNA, indicating that the A allele of
rs12742393 appears to be a risk allele associated with
SCZ that acts by enhancing transcription factor binding
and increasing gene expression [215]. Findings of an-
other study in the South American population are also
consistent with a role for NOS1AP in susceptibility to
SCZ, especially for the “negative syndrome” of the dis-
order [216].
NKCC1 and KCC2 (SLC12A2; SLC12A5). The na-
ture of γ-aminobutyric acid neurotransmission depends
on the local intracellular chloride concentration. In the
CNS, the intracellular chloride level is determined by the
activity of 2 cation-chloride transporters, NKCC1 and
KCC2. The activities of these transporters are in turn
regulated by a network of serine-threonine kinases that
includes OXSR1, STK39, and the WNK kinases WNK1,
WNK3, and WNK4. Arion and Lewis [217] compared
the levels of NKCC1, KCC2, OXSR1, STK39, WNK1,
WNK3, and WNK4 transcripts in prefrontal cortex area 9
between subjects with SCZ and healthy subjects. OXSR1
and WNK3 transcripts were substantially overexpressed
in subjects with schizophrenia relative to comparison
subjects. In contrast, NKCC1, KCC2, STK39, WNK1,
and WNK4 transcript levels did not differ between sub-
ject groups. OXSR1 and WNK3 transcript expression
levels were not changed in antipsychotic-exposed mon-
keys and were not affected by potential confounding
factors in the subjects with schizophrenia. According to
Arion and Lewis, in schizophrenia, increased expression
levels, and possibly increased kinase activities, of
OXSR1 and WNK3 may shift the balance of chloride
transport by NKCC1 and KCC2 and alter the nature of
γ-aminobutyric acid neurotransmission in the prefrontal
cortex.
NOGO-66 receptor 1 (RTN4R). SCZ or schizoaffec-
tive disorders are quite common features in patients with
DiGeorge/velo-cardio-facial syndrome (DGS/VCFS) as a
result of chromosome 22q11.21 haploinsufficiency. In
SCZ, genetic predisposition has been linked to chromo-
some 22q11, and myelin-specific genes are misexpressed
in SCZ. Nogo-66 receptor 1 (NGR or RTN4R) has been
considered to be a 22q11 candidate gene for SCZ suscep-
tibility because it encodes an axonal protein that medi-
ates myelin inhibition of axonal sprouting. The RTN4R
gene encodes a subunit of the receptor complex (RTN4R-
p75NTR) which results in neuronal growth inhibitory
signals in response to Nogo-66, MAG or OMG signaling.
RTN4R regulates axonal growth, as well as axon regen-
eration after injury. The gene maps to the 22q11.21 SCZ
susceptibility locus and is thus a strong functional and
positional candidate gene. RTN4R encodes for a func-
tional cell surface receptor, a glycosyl-phosphatidy-
linositol (GPI)-linked protein, with multiple leucine-rich
repeats (LRR), which is implicated in axonal growth
inhibition. Three mutant alleles were detected, including
two missense changes (c.355C > T; R119W and c.587G
> A; R196H), and one synonymous codon variant (c.54G
> A; L18L). Schizophrenic patients with the missense
changes were strongly resistant to the neuroleptic treat-
ment at any dosage. Both missense changes were absent
in 300 control subjects. Molecular modeling revealed
that both changes lead to putative structural alterations of
the native protein [218]. RTN4R deficiency can modu-
late the long-term behavioral effects of transient postna-
tal N-methyl-D-aspartate (NMDA) receptor hypofunc-
tion. Results reported by Meng et al. [219] and Hsu et al.
[220] do not support a major role of RTN4R in suscepti-
bility to SCZ or the cognitive and behavioral deficits
observed in individuals with 22q11 microdeletions;
however, they suggest that RTN4R may modulate the
genetic risk or clinical expression of SCZ in a subset of
patients.
Neuronal cultures demonstrate that four different SCZ-
derived NgR1 variants fail to transduce myelin signals
into axon inhibition, and function as dominant negatives
to disrupt endogenous NgR1. Mice lacking NgR1 protein
exhibit reduced working memory function, consistent
with a potential endophenotype of SCZ. For a restricted
subset of individuals diagnosed with SCZ, the expression
of dysfunctional NGR variants may contribute to in-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 99
creased disease risk [221].
NOTCH4. The NOTCH4 gene is located within the
major histocompatability complex region on chromo-
some 6p21.3 and sequence variants have shown asso-
ciation with SCZ. McDonald et al. [222] examined the
methylation status of a region surrounding the NOTCH4
−25C/T site in leukocyte genomic DNA and human brain
regions. They also studied the polymorphism status of
NOTCH4 −25C/T. −25C was the only cytosine which
showed methylation in any of the blood or brain samples
analyzed. −25C was always fully or partially methylated
in blood, was methylated in a similar pattern between
SCZ and controls in the blood and was variably methy-
lated in the brain, including completely methylated, par-
tially methylated, subtly methylated or not methylated.
–25C/T polymorphism was not associated to schizo-
phrenia. The polymorphism and methylation analysis of
NOTCH4 established that the −25C/T polymorphism and
methylation status is not associated with schizophrenia,
and that −25C is variably methylated in a regionspecific
manner in the brain.
NRXN1 (Neurexin 1). Copy number variants (CNVs)
and intragenic rearrangements of the NRXN1 (neurexin
1) gene are associated with a wide spectrum of develop-
mental and neuropsychiatric disorders, including intel-
lectual disability, speech delay, autism spectrum disor-
ders (ASDs), hypotonia and schizophrenia. Schaaf et al.
[223] performed a clinical and molecular characteriza-
tion of 24 patients who underwent clinical microarray
analysis and had intragenic deletions of NRXN1. 17 of
these deletions involved exons of NRXN1, whereas 7
deleted intronic sequences only. The patients with exonic
deletions manifested developmental delay/intellectual
disability (93%), infantile hypotonia (59%) and ASDs
(56%). The more C-terminal deletions, including those
affecting the β isoform of neurexin 1, manifested in-
creased head size and a high frequency of seizure disor-
der (88%) when compared with N-terminal deletions of
NRXN1.
OLIG2 (Oligodendrocyte lineage transcription fac-
tor 2). Psychotic symptoms are common in more than
10% of patients with AD and define a phenotype with
more rapid cognitive and functional decline. Oligoden-
drocyte lineage transcription factor 2 (OLIG2) is a regu-
lator of white matter development and a candidate gene
for SCZ [224], which may also be associated with psy-
chotic symptoms in AD. 11 SNPs in OLIG2 previously
tested for association with SCZ were tested for associa-
tion with AD. Significant evidence for association of
psychotic symptoms within cases was identified for the
SNPs rs762237 and rs2834072 [225]. Deficits in the ex-
pression of oligodendrocyte and myelin genes have been
described in numerous cortical regions in SCZ and affec-
tive disorders. mRNA expression of 17 genes expressed
by oligodendrocyte precursors (OLPs) and their deriva-
tives, including astrocytes, have been studied in four
subcortical regions (the anteroventral (AV) and medio-
dorsal thalamic nuclei (MDN), internal capsule (IC) and
putamen (Put)). Genes expressed after the terminal dif-
ferentiation of oligodendrocytes tended to have lower
levels of mRNA expression in subjects with SCZ com-
pared to controls. These differences were statistically
significant across regions for four genes (CNP, GALC,
MAG and MOG) and approached significance for TF.
Two astrocyte-associated genes (GFAP and ALDH1L1)
had higher mean expression levels across regions in SCZ.
Significant positive correlations were also observed in
some regions between cumulative neuroleptic exposure
and the expression of genes associated with mature oli-
godendrocytes as well as with bipotential OLPs [226].
PALB2 (Partner and localizer of BRCA2). A ge-
nome-wide association study (GWAS) found significant
association between the PALB2 SNP rs420259 and bipo-
lar disorder (BD). The intracellular functions of the ex-
pressed proteins from the breast cancer risk genes
PALB2 and BRCA2 are closely related. Tesli et al. [227]
investigated the relation between genetic variants in
PALB2 and BRCA2 and BD/SCZ in a Scandinavian
case-control sample and found the BRCA2 SNP
rs9567552 to be significantly associated with BD. When
they combined their sample with another Nordic case-
control sample from Iceland, and added results from the
Wellcome Trust Case Control Consortium (WTCCC) and
the STEP-UCL/ED- DUB-STEP2 study in a meta-
analysis, an association between PALB2 SNP rs420259
and BD was observed. Neither the PALB2 SNP rs420259
nor the BRCA2 SNP rs9567552 were nominally signifi-
cantly associated with the SCZ phenotype in the Scandi-
navian sample.
Pericentrin (PCNT). Pericentrin (PCNT) interacts
with DISC1, BD and major depressive disorder (MDD).
A significant allelic association has been found between
3 SNPs (rs3788265, rs2073376 and rs2073380) of the
PCNT gene and MDD. After correction for multiple
testing, 2 SNPs (rs3788265 and rs2073376) retained sig-
nificant allelic associations with MDD. A significant
association has also been detected between the 2 marker
haplotypes (r3788265 and rs2073376) and MDD. Ac-
cording to these results reported by Numata et al. [228],
genetic variations in the PCNT gene may play a role in
the etiology of MDD in the Japanese population.
Peroxisome proliferator-activated receptor gamma
(PPARG), PLAG2G4A, and PTGS2. Patients with
SCZ have an increased risk of type-2 diabetes. The com-
bined effects of the PLA2G4A, PTGS2 and PPARG
genes were tested among 221 British nuclear families
consisting of fathers, mothers and affected offspring with
SCZ. A total of 10 SNPs were tested and the likeli-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 100
hood-based association analysis for nuclear families was
used to analyze the genotyping data. Eight SNPs detected
across the PPARG gene did not show allelic association
with SCZ; a weak association was detected at rs2745557
in the PTGS2 locus and rs10798059 in the PLA2G4A
locus. The gene-gene interaction test did not show any
evidence of either cis-phase interactions for the
PLA2G4A and PTGS2 combinations or a trans-phase
interaction for the PLA2G4A and PPARG combinations.
The PPARG gene has been reported to be strongly asso-
ciated with type-2 diabetes, but the results reported by
Mathur et al. [229] did not support the hypothesis that
the PPARG gene may play a role in the development of
SCZ.
Phosphatidylinositol 4-kinase type-II beta (PI4K2B).
Linkage of BD and recurrent major depression with
markers on chromosome 4p15.2 has been identified in a
large Scottish family and three smaller families. Analysis
of haplotypes in the four chromosome 4p-linked families,
identified two regions, each shared by three of the four
families, which are also supported by a case-control as-
sociation study. The candidate gene phosphatidylinositol
4-kinase type-II beta (PI4K2B) lies within one of these
regions. PI4K2B is a strong functional candidate as it is a
member of the phosphatidylinositol pathway, which is
targeted by lithium for therapeutic effect in BD. A case-
control association study, using tagging SNPs from the
PI4K2B genomic region, in BD, SCZ and controls
showed association with a two-marker haplotype in SCZ
but not in BD (rs10939038 and rs17408391). Expression
studies at the allele-specific mRNA and protein level
using lymphoblastoid cell lines from members of the
large Scottish family, which showed linkage to 4p15.2 in
BD and recurrent major depression, showed no differ-
ence in expression differences between affected and
non-affected family members. There is no evidence to
suggest that PI4K2B is contributing to BD in this family
but a role for this gene in SCZ has not been excluded
[230].
Presenilin 2 (PSEN2). Mutations in the presenilin 1
(PSEN1) and PSEN2 genes are major causative factors
for AD [35]. Presenilins are a group of proteins playing
an important role in the Notch, ErbB4 and Wnt signaling
pathways which might also be associated with SCZ
and/or psychotic symptoms in dementia. The gene cod-
ing for presenilin 2 (PSEN2) is located on 1q31-q42 and
adjacent to a balanced translocation t (1; 11) (q42; q14.3)
that was found to co-segregate within family members of
patients with SCZ. Five functional SNPs (rs1295645,
rs11405, rs6759, rs1046240 and rs8383) present in the
coding regions of the PSEN2 gene were tested in 410
patients with SCZ and 355 controls in a Chinese Han
population. Association analysis showed a weak associa-
tion for rs1295645, and the rs1295645-T allele was in-
volved in increased risk of SCZ. The T-C-T-T-T haplo-
type also showed association with increased risk of SCZ.
Analysis of gene expression demonstrated that PSEN2
mRNA levels in peripheral leukocytes were significantly
lower in SCZ than in controls and that expression levels
of the PSEN2 gene were significantly correlated to its
genotypes. Analysis of clinical profiles showed an asso-
ciation between the PSEN2 gene and some clinical phe-
notypes scored using the PANSS. The PSEN2 gene may
be a novel candidate involved in the development of cer-
tain psychotic symptoms in SCZ [231].
Proline dehydrogenase/proline oxidase (PRODH).
Significant associations have been shown for haplotypes
comprising three PRODH SNPs: 1945T/C, 1766A/G, and
1852G/A, located in the 3’ region of the gene, suggesting
a role of these variants in the pathogenesis of SCZ. Stud-
ies on prepulse inhibition (PPI), verbal and working
memory, trait anxiety and schizotypy indicate that CGA
carriers exhibit attenuated PPI and verbal memory to-
gether with higher anxiety and schizotypy compared with
noncarriers [232].
Quaking homolog, KH doma in RNA binding (QKI).
Chromosome 6q26 includes a susceptibility locus for
SCZ in a large pedigree from northern Sweden. Aberg et
al. [233] fine-mapped a 10.7 Mb region, included in this
locus, using 42 microsatellites or SNP markers, and
found a 0.5 Mb haplotype, within the large family that is
shared among the majority of the patients (69%). A gam-
ete competition test of this haplotype in 176 unrelated
nuclear families from the same geographical area as the
large family showed association to SCZ. The only gene
located in the region, the quaking homolog, KH domain
RNA binding (mouse) (QKI), was investigated in human
brain autopsies. Relative mRNA expression levels of two
QKI splice variants were clearly downregulated in
schizophrenic patients. The mouse homolog is involved
in neural development and myelination [233]. Disturbed
QKI mRNA expression is observed in the prefrontal cor-
tex of patients, and some of these changes correlate to
treatment with antipsychotic drugs. In human astrocy-
toma (U343) and oligodendroglioma (HOG) cell lines
treated with five different antipsychotic drugs including
haloperidol, aripiprazole, clozapine, olanzapine and
risperidone, haloperidol treatment doubled QKI-7 mRNA
levels in U343 cells after 6 hours. The effect was
dose-dependent, and cells treated with ten times higher
concentration responded with a five-fold and three-fold
increase in QKI-7, 6 and 24 hours after treatment, re-
spectively. QKI-7 mRNA expression in human astrocytes
is induced by haloperidol, at concentrations similar to
plasma levels relevant to clinical treatment of SCZ [234].
RANBP1 (RAN-binding protein 1). Smooth pursuit
eye movement (SPEM) disturbance is proposed as one of
the most consistent neurophysiological endophenotypes

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 101
in SCZ. Cheong et al. [235] examined the genetic asso-
ciation of RANBP1 polymorphisms (22q11.21) with the
risk of SCZ and with the risk of SPEM abnormality in
schizophrenic patients in a Korean population. No
RANBP1 polymorphisms were associated with the risk
of schizophrenia; however, a common haplotype,
RANBP1-ht2 (rs2238798G-rs175162T), showed signifi-
cant association with the risk of SPEM abnormality
among schizophrenic patients.
Reelin (RELN). Reelin is a large secreted protein of
the extracellular matrix that has been proposed to par-
ticipate to the etiology of SCZ. The reelin gene (RELN)
encodes a secretory glycoprotein critical for brain de-
velopment and synaptic plasticity. Post-mortem studies
have shown lower reelin protein levels in the brains of
patients with SCZ and BP compared with controls. In a
genome-wide association study of SCZ, the strongest
association was found in a marker within RELN, al-
though this association was seen only in women. RELN
is also associated with BP in women [236]. Several au-
thors successfully replicated SCZ linkage on chromo-
some 7q22 in different populations and demonstrated
that an intragenic short tandem repeat (STR) allele of the
regional RELN gene is associated with multiple cogni-
tive traits representing central cognitive functions re-
garded as valid endophenotypes for SCZ. There is asso-
ciation between RELN intragenic STR allele and work-
ing memory, impaired cognitive functioning and more
severe positive and negative symptoms of SCZ [237].
Reelin plays a pivotal role in neurodevelopment. Exces-
sive RELN promoter methylation and/or decreased
RELN gene expression have been described in SCZ and
autism. Temporocortical tissue (Brodmann’s area 41/42)
of postpuberal individuals is heavily methylated, espe-
cially at CpG positions located between −131 and −98 bp.
Sex hormones thus seemingly boost DNA methylation at
the RELN promoter. This physiological mechanism
might contribute to the onset of SCZ and the worsening
of autistic behaviors during the puberal period [238].
During development, reelin is crucial for the correct cy-
toarchitecture of laminated brain structures and is pro-
duced by a subset of neurons named Cajal-Retzius. After
birth, most of these cells degenerate and reelin expres-
sion persists in postnatal and adult brain. In hippocampal
cultures, reelin is secreted by GABAergic neurons dis-
playing an intense reelin immunoreactivity (IR). Secreted
reelin binds to receptors of the lipoprotein family on
neurons with punctate reelin IR. Blocking protein secre-
tion rapidly and reversibly changes the subunit composi-
tion of N-methyl-D-aspartate glutamate receptors
(NMDARs) to a predominance of NR2B-containing
NMDARs. Addition of recombinant or endogenously
secreted reelin rescues the effects of protein secretion
blockade and reverts the fraction of NR2B-containing
NMDARs to control levels. The continuous secretion of
reelin is necessary to control the subunit composition of
NMDARs in hippocampal neurons. Defects in reelin
secretion could play a major role in the development of
neuropsychiatric disorders, particularly those associated
with deregulation of NMDARs such as SCZ [239].
Reelin is down-regulated in the brain of schizophrenic
patients and of heterozygous reeler mice (rl/+). The be-
havioral phenotype of rl/− mice, however, matches only
partially the SCZ hallmarks. Homozygous reeler mutants
(rl/rl) exhibit reduced density of parvalbumin-positive
(PV+) GABAergic interneurons in anatomically circum-
scribed regions of the neostriatum. The striatal regions in
which rl/rl mice exhibited decreased density of PV+ in-
terneurons are either unaltered (rostral striatum) or equal-
ly altered (dorsomedial and ventromedial intermediate
striatum, caudal striatum) in rl/+ mice. Reelin haploin-
sufficiency alters the density of PV+ neurons in circum-
scribed regions of the striatum and selectively disrupts
behaviors sensitive to dysfunction of these targeted re-
gions [240]. Brain abnormalities in +/rl are similar to the
psychotic brain and include a reduction in glutamic acid
decarboxylase 67 (GAD67), dendritic arbors and spine
density in cortex and hippocampus, and abnormalities in
synaptic function including long-term potentiation (LTP).
RELN and GAD67 promoters are hypermethylated in
GABAergic neurons of psychotic post-mortem brain and
DNA methyltransferase 1 (DNMT1) is up-regulated.
Hypermethlyation of RELN and GAD67 promoters can
be induced by treating mice with methionine, and these
mice display brain and behavioral abnormalities similar
to +/rl [241,242].
Selenium binding protein 1 (SELENBP1). The
SELENBP1 gene was found to be up-regulated in both
peripheral blood cell and brain tissue samples from SCZ
patients. One of four haplotype-tagging SNPs and two
different two-marker haplotypes showed nominally sig-
nificant evidence for association with SCZ in Han Chi-
nese patients living in Taiwan [243].
Serine racemase. D-Serine is an important NMDAR
modulator. The D-serine synthesis enzyme serine race-
mase (SRR) has been found to be defective in SCZ. Mice
with an ENU-induced mutation that results in a complete
loss of SRR activity exhibit dramatically reduced
D-serine levels. Mutant mice displayed behaviors rele-
vant to SCZ, including impairments in prepulse inhibi-
tion, sociability and spatial discrimination. Behavioral
deficits were exacerbated by an NMDAR antagonist and
ameliorated by D-serine or the atypical antipsychotic
clozapine. Expression profiling revealed that the SRR
mutation influenced several genes that have been linked
to SCZ and cognitive ability. Transcript levels altered by
the SRR mutation were also normalized by D-serine or
clozapine treatment. Analysis of SRR genetic variants in

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 102
humans identified a potential association with SCZ. Ab-
errant Srr function and diminished D-serine may con-
tribute to SCZ pathogenesis [244].
Serotonin 6 (5-HT6) receptors (HTR6). Genetic al-
terations in serotonin 6 (5-HT6) receptors might be asso-
ciated with the pathophysiology of SCZ. Kishi et al. [245]
conducted an association study of the HTR6 gene
(rs1805054 (C267T)) in Japanese patients and found no
significant associations between the tagging SNPs in
HTR6 and SCZ. In a meta-analysis of rs1805054, draw-
ing data from five studies, rs1805054 was not associated
with SCZ.
Serotonin (5-Hydroxytryptamine (5-HT)) trans-
porter (SLC6A4). Serotonin (5-hydroxytryptamine
(5-HT)) transporter (SLC6A4) is known to influence
mood, emotion, cognition and efficacy of antidepressants,
particularly that of selective serotonin reuptake inhibitors.
Atypical antipsychotics exert their effects partially
through serotonergic systems, and hence, variation in
5-HT uptake may affect antipsychotic action mediated
through the serotonergic system. The genetic roles of
five polymorphisms of SLC6A4, including those of the
widely studied 44 base pair variable number of tandem
repeat (VNTR) in the promoter region of SLC6A4 (the
serotonin transporter gene-linked polymorphic region:
5HTTLPR) and a VNTR polymorphism (STin2) in the
second intron, have been studied in SCZ. Significant
allelic and genotypic associations with rs2066713,
5HTTLPR and STin2 polymorphisms have been detected.
A haplotype linking these three risk alleles, 5HTTLPR/
S-rs2066713/C-STin2/12-repeat, was also significantly
associated with SCZ in a South Indian population [246].
A common polymorphism STin2 VNTR in the 5-HTT
gene has been extensively investigated in genetic asso-
ciation studies. Lin et al. [247] conducted a case-control
study of the association between STin2 VNTR and three
tagging SNPs in 5-HTT and SCZ in the Han Chinese
population and no association was found in the single
locus, but haplotype-based analyses revealed significant
association between two haplotypes with SCZ [247]. A
44 base pair insertion (“l”)/deletion (“s”) polymorphism
(called 5-HTTLPR) in the 5’ promoter region of the hu-
man serotonin transporter gene modulates expression and
has been associated to anxiety and depressive traits in
otherwise healthy individuals. In individuals with SCZ it
seems to modulate symptom severity, acting as a disease
modifying gene. In dominant models, the 5-HTTLPR
genotype accounted for a significant portion of the vari-
ance in SCID depression and SANS negative symptoms
(about 5%). The l allele was associated with greater psy-
chopathology and the s allele was associated with greater
anxiety and depression levels. Allelic variation may have
different consequences for personality traits or psychiat-
ric symptoms depending on epistasis or epigenetic con-
text [248]. The serotonin transporter-linked polymorphic
region (5-HTTLPR) short allele confers a general sensi-
tivity to environmental stimuli, and anger is suspected to
have a direct influence on aggressive behavior in SCZ.
The 5-HTTLPR gene was associated with aggression
and/or anger-related traits in SCZ; however, there was no
significant difference in the distribution of the 5-
HTTLPR genotype/alleles between the aggressive and
nonaggressive patients. Aggressive patients carrying the
s allele exhibited more anger-related traits than those
with the l/l homozygotes, but this difference was not
significant after correction for multiple testing. 5-
HTTLPR predisposes aggressive patients to exhibit more
anger-related traits, but there is no association between
5-HTTLPR and aggressive behavior in SCZ [249].
SH2B1 (SH2B adaptor protein 1). The short arm of
chromosome 16 is rich in segmental duplications, pre-
disposing this region of the genome to a number of re-
current rearrangements. Genomic imbalances of an ap-
proximately 600-kb region in 16p11.2 (29.5 - 30.1 Mb)
have been associated with autism, intellectual disability,
congenital anomalies, and SCZ. A separate, distal 200-kb
region in 16p11.2 (28.7 - 28.9 Mb) that includes the
SH2B1 gene has been associated with isolated obesity.
Bachmann-Gagescu et al. [250] studied the phenotype of
this recurrent SH2B1-containing microdeletion in a co-
hort of phenotypically abnormal patients with develop-
mental delay. Deletions of the SH2B1-containing region
were identified in 31 patients. The deletion is enriched in
the patient population when compared with controls,
with both inherited and de novo events. Body mass index
was ≥95th percentile in four of six patients, supporting
the previously described association with obesity. Ac-
cordingly, it appears that deletions of the 16p11.2 SH2B1-
containing region are pathogenic and are associated with
developmental delay in addition to obesity.
SHMT1 (Serine hydroxymethyltransferase, cytoso-
lic). NMDA receptor function affects PPI integrity and
D-serine and glycine are endogenous co-agonists for the
receptor. A quantitative trait loci analysis using C57BL/6
(B6) mice with better PPI performance and C3H/He (C3)
with lower PPI score has been reported. Genes for both
D-serine synthesizing enzyme and enzyme for reversible
conversion between glycine and L-serine (SRR and
SHMT1, respectively) are located in the same PPI-quan-
titative trait loci peak. Maekawa et al. [251] analyzed
expression levels and genetic polymorphisms of the two
genes. There were promoter polymorphisms in SHMT1,
which elicit lower transcriptional activity in B6 com-
pared to C3 conforming to the results of brain expression
levels, but no functional genetic variants in SRR. SHMT1
levels were higher in schizophrenic brains compared to
controls, with no changes in SRR levels. A nominal as-
sociation between SHMT1 and SCZ has been suggested.

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 103
Shmt1 (SHMT1), but not Srr, is likely to be one of the
genetic components regulating PPI in mice and possibly
relevant to SCZ.
Sialyltransferase 8B (ST8SIA2). McAuley et al. [252]
identified a significant bipolar spectrum disorder linkage
peak on 15q25-26 using 35 extended families with a
broad clinical phenotype, including bipolar disorder
(types I and II), recurrent unipolar depression and schi-
zoaffective disorder. By a fine mapping association study
in an Australian case-control cohort, they found that the
sialyltransferase 8B (ST8SIA2) gene, coding for an en-
zyme that glycosylates proteins involved in neuronal
plasticity which has previously shown association to both
schizophrenia and autism, is associated with increased
risk to bipolar spectrum disorder. Nominal single point
association was observed with SNPs in ST8SIA2
(rs4586379, rs2168351), and a specific risk haplotype
was identified. Using GWAS data from the NIMH bipo-
lar disorder and NIMH schizophrenia cohorts, the equi-
valent haplotype was significantly over-represented in
bipolar disorder, with the same direction of effect in SCZ.
Variation in the ST8SIA2 gene is associated with in-
creased risk to mental illness, acting to restrict neuronal
plasticity and disrupt early neuronal network formation,
rendering the developing and adult brain more vulnerable
to secondary genetic or environmental insults, according
to the Australian authors [252].
Sigma non-opioid intracellular receptor 1 (Sig-1R;
SIGMAR1). The sigma-1 receptor (Sig-1R) is engaged
in modulating NMDA and dopamine receptors which are
involved in the pathophysiology of SCZ and the mecha-
nism of psychotropic drug efficacy. Signals, detected
from prefrontal regions by 52-channel near-infrared spec-
troscopy (NIRS) during cognitive activation, were com-
pared between two Sig1-R genotype subgroups (Gln/Gln
individuals and Pro carriers) matched for age, gender,
premorbid IQ and task performance. The prefrontal
hemodynamic response of healthy controls during the
verbal fluency task was higher than that of patients with
SCZ. For the patients with SCZ, even after controlling
the effect of medication, the [oxy-Hb] increase in the
prefrontal cortex of the Gln/Gln genotype group was
significantly greater than that of the Pro carriers. Clinical
symptoms were not significantly different between the
two Sig-1R genotype subgroups. This was the first func-
tional imaging genetics study to implicate the association
between the Sig-1R genotype and prefrontal cortical
function in SCZ in vivo [253].
SLC6A3 (Solute carrier family 6 (neurotransmitter
transporter, Dopamine), member 3; Dopamine trans-
porter; DAT). Cordeiro et al. [254] reported an associa-
tion between a novel SNP (rs6347) located in exon 9 of
the dopamine transporter (SLC6A3) and SCZ.
SMARCA2/BRM and the SWI/SNF chromatin-
remodeling complex. Chromatin remodeling may play a
role in the neurobiology of SCZ. The SMARCA2 gene
encodes BRM in the SWI/SNF chromatin-remodeling
complex, and associations of SNPs with SCZ were found
in two linkage disequilibrium blocks in the SMARCA2
gene after screening of 11883 SNPs (rs2296212) and
subsequent screening of 22 genes involved in chromatin
remodeling (rs3793490) in a Japanese population. A risk
allele of a missense polymorphism (rs2296212) induced
a lower nuclear localization efficiency of BRM, and risk
alleles of intronic polymorphisms (rs3763627 and
rs3793490) were associated with low SMARCA2 ex-
pression levels in the post-mortem prefrontal cortex. A
significant correlation in the fold changes of gene ex-
pression from schizophrenic prefrontal cortex was seen
with suppression of SMARCA2 in transfected human
cells by specific siRNA, and of orthologous genes in the
prefrontal cortex of SMARCA2 knockout mice.
SMARCA2 knockout mice showed impaired social in-
teraction and prepulse inhibition. Psychotogenic drugs
lowered SMARCA2 expression while antipsychotic
drugs increased it in the mouse brain. According to Koga
et al. [255] these findings support the role of BRM in the
pathophysiology of SCZ.
SOX10 (SRY-BOX 10). A SNP (rs139887) in the sex-
determining region Y-box 10 (SOX10) gene, was sug-
gested to be associated with SCZ although inconsistent
results had been reported. Yuan et al. [256] evaluated the
association between SOX10 rs139887 polymorphism and
SCZ and three studies were selected for meta-analysis to
determine the effect of rs139887 on SCZ. The allele and
genotype frequencies were significantly different be-
tween schizophrenic patients and controls, and a signifi-
cant association in allele and genotype frequencies were
found in male patients, but not female patients. The C/C
genotype had a significant association with an earlier age
of onset in male schizophrenic patients, but not in female
patients. The meta-analysis showed that the same C al-
lele was significantly associated with SCZ.
SP4 transcription factor. The Sp4 transcription fac-
tor plays a critical role for both development and func-
tion of mouse hippocampus. Reduced expression of the
mouse Sp4 gene results in a variety of behavioral ab-
normalities relevant to human psychiatric disorders. The
human SP4 gene was examined for its association with
both BD and SCZ in European Caucasian and Chinese
populations respectively. Out of ten SNPs selected from
human SP4 genomic locus, four displayed significant
association with BD in European Caucasian families
(rs12668354; rs12673091; rs3735440; rs11974306). Four
SNPs displayed significant association (rs40245;
rs12673091; rs1018954; rs3735440) in the Chinese
population and two of them (rs12673091, rs3735440)
were shared with positive SNPs from European Cauca-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 104
sian families. Considering the genetic overlap between
BD and SCZ, extended studies in Chinese trio families
for SCZ revealed that SNP7 (rs12673091) also displayed
a significant association. SNP7 (rs12673091) was there-
fore significantly associated in all three samples, and
shared the same susceptibility allele (A) across all three
samples. A gene dosage effect for mouse Sp4 gene in the
modulation of sensorimotor gating, a putative endophe-
notype for both SCZ and BD, was also found. The defi-
cient sensorimotor gating in Sp4 hypomorphic mice was
partially reversed by the administration of a dopamine D2
antagonist or mood stabilizers. Both human genetic and
mouse pharmacogenetic studies support the Sp4 gene as
a susceptibility gene for BD or SCZ [257].
Spermidine/Spermine N1-acetyltransferase (SSAT1;
SAT1). Psychotic patients tend to show increased blood
and fibroblast total polyamine levels. Spermidine/sper-
mine N1-acetyltransferase (SSAT-1) and its coding gene
(SAT-1) are the main factors regulating polyamine ca-
tabolism. No association between the SAT-1 −1415T/C
SNP and SCZ was found in Spanish patients; however, a
mild association between allele C and psychopathology
was found in the female group [258].
Sulfotransferase 4A1 (SULT4A1). Sulfotransferase
4A1 (SULT4A1) is a novel sulfotransferase expressed
almost exclusively in the brain. The gene is located on
chromosome 22q13.2, a region implicated in predisposi-
tion to SCZ. A variable microsatellite region located up-
stream of SULT4A1 was found to be associated with an
increase in SCZ risk. If functional dysregulation of
SULT4A1 was involved in the etiology of SCZ, then ge-
netic variants in the coding sequence of SULT4A1 might
be identified in cases compared with controls. A mutation
analysis of the coding region (exons 2 - 7) in 71 Austra-
lian SCZ cases found no mutations, either synonymous
or nonsynonymous. However, intronic variants (IVS5 +
12 C > T and IVS5 + 28 G > C) were identified, the fre-
quency of which was not statistically different between
cases and controls. The lack of polymorphisms in the
coding region of the SULT4A1 gene is highly unusual
and, along with its high conservation between species,
suggests that SULT4A1 may have an important function
in vivo, but recent findings do not support the hypothesis
that germline mutations in the coding region of
SULT4A1 contribute to susceptibility to SCZ [259].
Synapsin 2-3 (SYN2, SYN3). The synapsin III gene
(SYN3), which belongs to the family of synaptic vesi-
cle-associated proteins, has been implicated in the
modulation of neurotransmitter release and in synapto-
genesis, suggesting a potential role in several neuropsy-
chiatric diseases. The human SYN3 gene is located on
chromosome 22q12-13, a candidate region implicated in
previous linkage studies of SCZ. Four SYN3 SNPs
(rs133945 (−631C > G), rs133946 (−196G > A), rs9862
and rs1056484) did not show association with SCZ in
either Irish or Chinese case-control samples [260]. Stud-
ies of SYN3 mRNA expression in human brain regions
as well as the methylation specificity in the closest CpG
island of this gene indicate that the cytosine methylation
in this genomic region is restricted to cytosines in CpG
dinucleotides, and is similar in brain regions and blood,
and appears conserved in primate evolution. Two cytosi-
nes (cytosine 8 and 20) localized as the CpG dinucleotide
are partially methylated in all brain regions. The methy-
lation of these sites in SCZ and control blood samples is
variable. The variation in SYN3 methylation is not re-
lated to SCZ or a monozygotic twin pair discordant for
SCZ and is not related to the mRNA level of SYN3a in
different human brain regions [261].
Synaptogyrin 1 (SYNGR1) . Synaptogyrin 1 (SYNGR1)
is a transmembrane protein of neurotransmitter-contain-
ing vesicle. Suggestive association between SYNGR1
intragenic polymorphisms and SCZ has been reported in
the Indian population. Rare nucleotide changes with a
potential pathogenic effect have been found in Indian and
Chinese SCZ patients. Evidence of association has been
found for rs715505 in the Italian population [262].
Polymorphisms of the synaptogyrin 1 (SYNGR1) and
synasin II (SYNII) genes have been shown to be a risk
factor for BD or SCZ. A case-control study with these
two genes was conducted in 506 BD patients and 507
healthy individuals from the Han Chinese population. No
association was found in this study [263].
Synaptosomal-associated protein 25 kDa (SNAP-
25). SNAP-25 (synaptosomal-associated protein of 25
kDa) is a plasma membrane protein that, together with
syntaxin and the synaptic vesicle protein VAMP/synap-
tobrevin, forms the SNARE (soluble N-ethylmaleimide-
sensitive factor attachment protein receptor) docking
complex for regulated exocytosis. SNAP-25 also modu-
lates different voltage-gated calcium channels, repre-
senting therefore a multifunctional protein that plays
essential roles in neurotransmitter release at different
steps. Recent genetic studies of human populations and
of some mouse models implicate alterations in SNAP-25
gene structure, expression, and/or function in contribut-
ing directly to these distinct neuropsychiatric and neuro-
logical disorders [264]. Both reduced and excessive
SNAP-25 activity has been implicated in various disease
states that involve cognitive dysfunctions such as ADHD,
SCZ and AD. Long-term memory is formed by altera-
tions in glutamate-dependent excitatory synaptic trans-
mission, which is in turn regulated by SNAP-25, a key
component of the SNARE complex essential for exocy-
tosis of neurotransmitter-filled synaptic vesicles. Excess
SNAP-25 activity, restricted to the adult period, is suffi-
cient to mediate significant deficits in the memory for-
mation process [265].

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 105
TAPASIN. Chlamydiaceae species has been identified
as a major factor in the pathogenesis of SCZ, suggesting
defective immune responses of schizophrenic patients
against this environmental factor. Immune responses
against Chlamydiaceae species are controlled by immu-
nogenetic factors. Successful responses against microbes
depend on the presentation of immunogenic peptides by
HLA molecules, which are encoded by a highly poly-
morphic gene system. Several HLA alleles or HLA anti-
gens have been found to be associated with SCZ in some
studies. It has been proposed that variants of these genes,
which control transportation and loading of microbial
peptides onto HLA molecules, could prevent clearing of
immune cell infection by selection of non-immunogenic
peptides for HLA presentation. To generate support for
this hypothesis, Fellerhoff and Wank [266] determined in
a small group of schizophrenic patients and control indi-
viduals allele frequencies of the transporter proteins
TAP1/TAP2, which select the immunoproteasome-tai-
lored peptides for transportation. Frequencies of TAPA-
SIN alleles, which encode chaperons and may also select
peptides for loading on MHC molecules, have also been
studied and significant associations between SCZ and
TAP1 allele frequencies as well as TAPASIN allele fre-
quencies were found, suggesting that variants of these
two genetic systems could influence SCZ. These genes
belong to the family of ABC transporter proteins and
may also influence the efficiency of drugs [266].
TATA box-binding protein gene (TBP). Spinocere-
bellar ataxia type 17 (SCA17) is a rare autosomal domi-
nant neurodegenerative disorder with ataxia and psy-
chotic symptoms. SCA17 is caused by an expanded po-
lyglutamine tract in the TATA box-binding protein (TBP)
gene. Ohi et al. [267] investigated the association be-
tween SCZ and CAG repeat length in common TBP al-
leles with fewer than 42 CAG repeats in a Japanese
population. A higher frequency of alleles with greater
than 35 CAG repeats was found in patients with SCZ
compared with that in controls. A negative correlation
between the number of CAG repeats in the chromosome
with longer CAG repeats out of two chromosomes and
age at onset of SCZ was also observed. TBP genotypes
with greater than 35 CAG repeats, which were enriched
in patients with SCZ, were significantly associated with
hypoactivation of the prefrontal cortex measured by
near-infrared spectroscopy during the tower of Hanoi, a
task of executive function. These findings suggest possi-
ble associations of the genetic variations of the TBP gene
with risk for SCZ, age at onset and prefrontal function
[267].
TDP-43 (TAR DNA-binding protein; TARDBP).
Clinical features of SCZ and BD overlap with some as-
pects of the behavioral variant of frontotemporal lobar
degeneration. The significance of pathological 43-kDa
(transactivation response) DNA-binding protein (TDP-43)
for frontotemporal lobar degeneration was recently sug-
gested. Geser et al. [268] studied patients with chronic
psychiatric diseases, mainly SCZ, for evidence of neu-
rodegenerative TDP-43 pathology in comparison with
controls. Significant TDP-43 pathology in the amyg-
dala/periamygdaloid region or the hippocampus/tran-
sentorhinal cortex was absent in both groups in subjects
younger than 65 years but present in elderly subjects
(29%) of the psychiatric patients and 29% of control
subjects. Twenty-three percent of the positive cases
showed significant TDP-43 pathology in extended brain
scans. There were no evident differences between the 2
groups in the frequency, degree, or morphological pattern
of TDP-43 pathology. The latter included subpial and
subependymal, focal, or diffuse lesions in deep brain
parenchyma and perivascular pathology. A new GRN
variant of unknown significance (c.620T > C, p.Met207Thr)
was found in one patient with SCZ with TDP-43 pathol-
ogy. No known TARDBP mutations or other variants
were found in any of the subjects studied. The similar
findings of TDP-43 pathology in elderly patients with
severe mental illness and controls suggest common
age-dependent TDP-43 changes in limbic brain areas that
may signify that these regions are affected early in the
course of a cerebral TDP-43 multisystem proteinopathy.
Transcription factor 4 (TCF4). A marker in intron 4
of the transcription factor 4 (TCF4) on 18q21.1
(rs9960767-C) has been associated with SCZ [269]. The
risk allele control frequency of this marker is about 6%.
TCF4 is essential for normal brain development. Muta-
tions in this gene were found to be responsible for
Pitt-Hopkins syndrome, an autosomal-dominant neuro-
developmental disorder characterized by mental and
psychomotor retardation, microcephaly, epilepsy and
facial dysmorphism.
Tripartite motif protein 32 (TRIM32). Mutations in
the gene encoding tripartite motif protein 32 (TRIM32)
cause two seemingly diverse diseases: limb-girdle mus-
cular dystrophy type 2H (LGMD2H) or sarcotubular
myopathy (STM) and Bardet-Biedl syndrome type 11
(BBS11). TRIM32 is involved in protein ubiquitination,
acting as a widely-expressed ubiquitin ligase, localized
to the Z-line in skeletal muscle. TRIM32 binds and ubiq-
uitinates dysbindin, a protein implicated in the genetic
etiology of SCZ, augmenting its degradation. Small-in-
terfering RNA-mediated knockdown of TRIM32 in
myoblasts resulted in elevated levels of dysbindin. The
LGMD2H/STM-associated TRIM32 mutations, D487N
and R394H, impair ubiquitin ligase activity towards dys-
bindin and were mislocalized in heterologous cells.
These mutants were able to self-associate and also
co-immunoprecipitated with wild-type TRIM32 in trans-
fected cells. D487N mutant could bind to both dysbindin

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 106
and its E2 enzyme but was defective in monoubiquitina-
tion. The BBS11 mutant P130S did not show any bio-
chemical differences compared with the wild-type pro-
tein. TRIM32 is a regulator of dysbindin and LGMD2H/
STM mutations may impair substrate ubiquitination
[270].
Tyrosine 3-monooxygenase/tryptophan 5-monooxy-
genase Activation Protein, Eta Isoform (YWHAH).
Brain protein 14-3-3, eta isoform, or tyrosine 3-mono-
oxygenase/tryptophan 5-monooxygenase activation pro-
tein 1 (YWHAH; 14-3-3-ETA) is a protein kinase-de-
pendent activator of tyrosine and tryptophan hydroxyl-
lases and an endogenous inhibitor of protein kinase C.
The 14-3-3 protein exists in several distinct forms: beta
(YWHAB), gamma (YWHAG), epsilon (YWHAE), zeta
(YWHAZ), theta (YWHAQ), sigma (SFN), and eta
(YWHAH). YWHAH is a positional and functional can-
didate gene for both SCZ and BP. This gene has previ-
ously been shown to be associated with both disorders,
and the chromosome location (22q12.3) has been re-
peatedly implicated in linkage studies for these disorders.
It codes for the eta subtype of the 14-3-3 protein family,
is expressed mainly in brain, and is involved in HPA axis
regulation. Five tag SNPs and the (GCCTGCA)n poly-
morphic locus present in this gene have been genotyped
and the rs2246704 SNP was associated with BP and
psychotic BP. The polymorphic repeat and two other
SNPs were also modestly associated with psychotic BP
[271].
Vitamin D-related genes. According to Amato et al.
[272], many natural phenomena are directly or indirectly
related to latitude. Living at different latitudes, indeed,
has its consequences with being exposed to different
climates, diets, or light/dark cycles. In humans, one of
the best known examples of genetic traits following a
latitudinal gradient is skin pigmentation. The authors
investigated latitude-driven adaptation phenomena, for
the first time on a wide genomic scale. They selected a
set of genes showing signs of latitude-dependent popula-
tion differentiation and studied whether genes associated
with neuropsychiatric diseases were enriched by Lati-
tude-Related Genes (LRGs). With this strategy, they
found a strong enrichment of LRGs in the set of genes
associated to SCZ, especially a set of vitamin D-related
genes.
X-ray repair complementing defective repair in
Chinese hamster cells 1 (XRCC1) and 4 (XRCC4).
Human cells fused with Chinese hamster ovary (CHO)
mutant lines, defective at different genes for excision
repair of DNA following ultraviolet (UV) irradiation or
defective in repair following X-irradiation, produce hy-
brids that retain the human gene that complements the
defect in the CHO line when selected under conditions
that require repair. The 1893-bp open reading frame of
this gene encodes a protein of 631 amino acids, com-
pared with the 633-amino acid polypeptide of human
XRCC1, which shares 86% sequence identity with
mouse proteins. An association between genetic poly-
morphism of XRCC1 Arg194Trp and risk of SCZ has
been reported [273].
Genetic factors related to the regulation of apoptosis in
schizophrenic patients may be involved in a reduced
vulnerability to cancer. XRCC4 is one of the potential
candidate genes associated with SCZ which might induce
colorectal cancer resistance. To examine the genetic as-
sociation between colorectal cancer and schizophrenia,
Wang et al. [274] analyzed five SNPs (rs6452526,
rs2662238, rs963248, rs35268, rs2386275) covering
~205.7 kb in the region of XRCC4. Two of the five ge-
netic polymorphisms (rs6452536, rs35268) showed sta-
tistically significant differences between 312 colorectal
cancer subjects without SCZ and 270 schizophrenic sub-
jects. The haplotype which combined all five markers
was the most significant. XRCC4 may be a potential pro-
tective gene towards SCZ, conferring reduced suscepti-
bility to colorectal cancer in the Han Chinese population.
YWHAE (Tyrosine 3-monooxygenase/tryptophan
5-monooxygenase activation protein, epsilon isoform;
14-3-3 epsilon protein). YWHAE is a gene encoding
14-3-3 epsilon, which is highly conserved across species,
from bacteria to humans, and binds to phosphoser-
ine/phosphothreonine motifs in a sequence-specific man-
ner. YWHAE has been reported to be associated with
SCZ in a study based on the Japanese population. Liu et
al. [275] conducted a genetic association analysis be-
tween common SNPs in the YWHAE gene and psy-
chiatric diseases including SCZ, major depressive disor-
der and bipolar disorder in Han Chinese samples (1140
schizophrenia cases, 1140 major depressive disorder
cases, 1140 bipolar disorder cases and 1140 normal con-
trols). Of the 11 SNPs studied, 7 had previously been
reported as significant in YWHAE. No association was
found with SCZ, major depressive disorder or bipolar
disorder. Considering the size of this sample set, these
results suggest that YWHAE does not play a major role
in SCZ, major depressive disorder or bipolar disorder in
the Han Chinese population.
Zinc finger protein 804A (ZNF804A). Two recent
genome-wide association studies reported association
between SCZ and the ZNF804A gene on chromosome
2q32.1 (rs1344706, rs7597593, rs1344706) [214]. The
associated SNP rs1344706 lies in approximately 30 bp of
conserved mammalian sequence, and the associated A
allele is predicted to maintain binding sites for the brain-
expressed transcription factors MYT1l and POU3F1/
OCT-6. In controls, expression is significantly increased
from the A allele of rs1344706 compared with the C al-
lele. Expression is increased in schizophrenic cases

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 107
compared with controls, but this difference does not
achieve statistical significance. This study replicates the
original reported association of ZNF804A with SCZ and
suggests that there is a consistent link between the A al-
lele of rs1344706, increased expression of ZNF804A and
risk for SCZ [276].
ZNF804A rs1344706 is the first genetic risk variant to
achieve genome-wide significance for psychosis. Fol-
lowing earlier evidence that patients carrying the
ZNF804A risk allele had relatively spared memory func-
tion compared to patient non-carriers, Donohoe et al.
[277] investigated whether ZNF804A was also associ-
ated with variation in brain volume. In a sample of 70
patients and 38 healthy participants they used voxel-
based morphometry to compare homozygous (AA) car-
riers of the ZNF804A risk allele to heterozygous and
homozygous (AC/CC) non-carriers for both whole brain
volume and specific regions implicated in earlier
ZNF804A studies (the dorsolateral pre-frontal cortex, the
hippocampus, and the amygdala). Homozygous SCZ
“AA” risk carriers had relatively larger gray matter vol-
umes than heterozygous/homozygous non-carriers (AC/CC),
particularly for hippocampal volumes. ZNF804A might
be delineating a SCZ subtype characterized by relatively
intact brain volume.
Dwyer et al. [278] undertook a study to identify
whether rare (frequency ~0.001%) coding variants in the
SCZ susceptibility gene ZNF804A are involved in this
psychotic disorder. No single rare variant was associated
with SCZ, nor was the burden of rare, or even fairly
common, non-synonymous variants. These results do not
support the hypothesis that moderately rare non-syn-
onymous variants at the ZNF804A locus are involved in
schizophrenia susceptibility.
As the first gene to have achieved genome-wide sig-
nificance for psychosis, ZNF804A has predictably been a
subject of intense research activity. Donohoe et al. [279]
reviewed the evidence to date for the association be-
tween SCZ and the original risk variant rs1344706, as
well as additional common and rare variants at this locus,
and concluded that ZNF804A is robustly, if modestly,
associated with SCZ risk.
For markers rs4667000 and rs1366842, significant
differences in allele frequencies were found between
cases and controls in the Chinese Han population. Ana-
lysis of haplotype rs61739290-rs1366842 showed sig-
nificant association with SCZ. A meta-analysis com-
prised of studies that utilized sample sets of either Euro-
pean and/or Han Chinese origin revealed statistically
significant associations for two SNPs (rs1366842,
rs3731834) and SCZ.
MicroRNAs (miRNAs) are small non-coding RNAs
that mainly function as negative regulators of gene ex-
pression and have been shown to be involved in schizo-
phrenia etiology through genetic and expression studies.
A polymorphism (rs1625579) located in the primary
transcript of a miRNA gene, hsa-miR-137, was reported
to be strongly associated with SCZ. Four SCZ loci
(CACNA1C, TCF4, CSMD1, C10orf26) were predicted
as hsa-miR-137 targets, and Kim et al. [280] showed that
ZNF804A is also a target for hsa-miR-137.
3.3. Copy Number Variants and Cytogenetic
Anomalies
The mechanisms underlying generation of neuronal va-
riability and complexity still remain enigmatic, and rep-
resent the central challenge for neuroscience. Structural
variation in the neuronal genome is likely to be a rele-
vant feature of neuronal diversity and brain dysfunction.
Large-scale genomic variations due to loss or gain of
whole chromosomes (aneuploidy) have been described in
cells of the normal and diseased human brain, which are
generated from neural stem cells during the intrauterine
period of life. In studies with more than 600,000 neural
cells, it has been found that the average aneuploidy fre-
quency is 1.25% - 1.45% per chromosome, with the
overall percentage of aneuploidy tending to approach
30% - 35%, and that mosaic aneuploidy may be exclu-
sively confined to the brain. These findings might indi-
cate that 1) aneuploidization could be an additional
pathological mechanism for neuronal genome diversifi-
cation; 2) aneuploidy is involved in brain development;
and 3) a link between developmental chromosomal in-
stability and intercellular/intertissular genome diversity
might be associated with pathogenic mechanisms under-
lying specific CNS disorders [281].
Using DNA probes for chromosomes 1, 7, 11, 13, 14,
17, 18, 21, X and Y, the mean rate of stochastic aneup-
loidy per chromosome is 0.5% in the normal human
brain. The overall proportion of aneuploid cells in the
normal brain has been estimated at approximately 10%.
The overall proportion of aneuploid cells in the brain of
patients with ataxia-telangiectasia was estimated at ap-
proximately 20% - 50%. A dramatic 10-fold increase of
chromosome 21-specific aneuploidy (both hypoploidy
and hyperploidy) was detected in the AD cerebral cortex
(6% - 15% vs 0.8% - 1.8% in control). It appears that
somatic mosaic aneuploidy differentially contributes to
intercellular genomic variation in the brain, probably
influencing brain dysfunction and neurodegeneration
[282].
Brain aneuploidy was hypothesized to be involved in
the pathogenesis of SCZ. In normal brains, average fre-
quencies of stochastic chromosome 1 loss and gain were
0.3% and 0.3%, respectively, with a threshold level for
stochastic chromosome gain and loss of 0.7%. Average
rate of aneuploidy in SCZ brains is 0.9% for chromo-
some 1 loss and 0.9% for chromosome 1 gain. Signifi-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 108
cantly increased level of mosaic aneuploidy involving
chromosome 1 was revealed in brains (3.6% and 4.7% of
cells with chromosome 1 loss and gain, respectively).
Stochastic aneuploidy rate for chromosome 1 in SCZ
brains reached 0.6% for loss and 0.5% for gain and was
higher than in controls, suggesting that subtle genomic
imbalances manifesting as low-level mosaic aneuploidy
may contribute to SCZ pathogenesis [283].
Copy number variants (CNVs) have been identified in
individual patients with SCZ and also in neurodevelop-
mental disorders [284]. A genome-wide survey of rare
CNVs in 3391 patients with SCZ and 3181 ancestrally
matched controls, using high-density microarrays, de-
tected CNVs in less than 1% of the sample with 100 kb
in length. The total burden was increased 1.15-fold in
patients with SCZ in comparison with controls. Deletions
were found within the region critical for velo-cardio-
facial syndrome, which includes psychotic symptoms in
30% of patients. Associations with SCZ were also found
for large deletions on chromosome 15q13.3 and 1q21.1
[184]. CNVs have been shown to increase the risk to
develop SCZ. The best supported findings are at 1q21.1,
15q11.2, 15q13.3, 16p13.1, 16p13.11 and 22q11.2, and
deletions at the gene neurexin 1 (NRXN1). In the Japa-
nese population, as in other Western populations, there is
a trend for excess of rare CNVs in SCZ; however, previ-
ously implicated association for very large CNVs (>500
kb) could not be confirmed in this population [285]. In a
genome-wide search for CNVs associating with SCZ, 66
de novo CNVs were identified in a sample of 1433 SCZ
cases and 33250 controls. Three deletions at 1q21.1,
15q11.2 and 15q13.3 showing nominal association with
SCZ in the first sample (phase I) were followed up in a
second sample of 3285 cases and 7951 controls (phase
II). All three deletions significantly associate with SCZ
and related psychoses in the combined sample [208].
There are 484 annotated genes located on 8p; many
are most likely oncogenes and tumor-suppressor genes.
Molecular genetics and developmental studies have iden-
tified 21 genes in this region (ADRA1A, ARHGEF10,
CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2,
EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2,
NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and
VMAT1/SLC18A1) that are most likely to contribute to
neuropsychiatric disorders (SCZ, autism, BD and de-
pression), neurodegenerative disorders (Parkinson’s and
Alzheimer diseases) and cancer. At least seven nonpro-
tein-coding RNAs (microRNAs) are located at 8p.
Structural variants on 8p, such as copy number variants,
microdeletions or microduplications, might also contrib-
ute to autism, SCZ and other human diseases including
cancer [286]. A genome-wide assessment of SNPs and
CNVs in 1460 patients with SCZ and 12,995 controls of
European ancestry identified 8 cases and zero controls
with deletions greater than 2 Mb, of which two, at 8p22
and 16p13.11-p12.4, were novel. A further evaluation of
1378 controls identified no deletions greater than 2 Mb,
suggesting a high prior probability of disease involve-
ment when such deletions are observed in cases. Further
evidence for some smaller SCZ-associated CNVs, such
as those in NRXN1 and APBA2, was confirmed; how-
ever, this study could not provide strong support for the
hypothesis that SCZ patients have a significantly greater
“load” of large (>100 kb), rare CNVs, nor could it find
common CNVs that associate with SCZ or SCZ-associ-
ated CNVs that disrupt genes in neurodevelopmental
pathways [287].
Kirov et al. [288] investigated the involvement of rare
(<1%) copy number variants (CNVs) in 471 cases of
SCZ and 2792 controls that had been genotyped using
the Affymetrix GeneChip 500K Mapping Array. Large
CNVs >1 Mb were 2.26 times more common in cases,
with the effect coming mostly from deletions, although
duplications were also more common. Two large dele-
tions were found in two cases each, but in no controls: a
deletion at 22q11.2 known to be a susceptibility factor
for SCZ and a deletion on 17p12, at 14.0 - 15.4 Mb. The
latter is known to cause hereditary neuropathy with li-
ability to pressure palsies. The same deletion was found
in 6 of 4618 (0.13%) cases and 6 of 36,092 (0.017%)
controls in the re-analyzed data of two recent large CNV
studies of SCZ. One large duplication on 16p13.1, which
has been previously implicated as a susceptibility factor
for autism, was found in three cases and six controls
(0.6% vs 0.2%). This study also provided the first sup-
port for a recently reported association between deletions
at 15q11.2 and SCZ [288]. A susceptibility locus in
13q13-q14 is shared by SCZ and mood disorder, and that
locus would be additional to another well-documented
and more distal 13q locus where the G72/G30 gene is
mapped [289].
Idiopathic generalized epilepsies account for 30% of
all epilepsies. Microdeletions at 15q13.3 have recently
been shown to constitute a strong genetic risk factor for
common idiopathic generalized epilepsy syndromes,
implicating that other recurrent microdeletions may also
be involved in epileptogenesis. Five microdeletions at
the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2,
16p13.11 and 22q11.2 represent genetic risk to common
idiopathic generalized epilepsy syndromes and other
neuropsychiatric disorders [290]. Microdeletion at
chromosomal position 15q13.3 has been described in
intellectual disability, autism spectrum disorders, SCZ
and in idiopathic generalized epilepsy [291]. The pheno-
typic profile of children with microdeletions of 15q13.3
includes developmental delay, mental retardation, or
borderline IQ, autistic spectrum disorder, speech delay,
aggressiveness, attention-deficit hyperactivity disorder,

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 109
and other behavioral problems [292]. Positive genetic
linkage to the 15q13-q14 region has been found in many
studies, and several association reports support this locus
as a candidate region for SCZ. A candidate gene in the
region, the alpha7 nicotinic receptor CHRNA7, plays a
seminal role in the linked endophenotype, and is de-
creased in expression in the patient population. The
15q13-q14 region contains a partial duplication of the
CHRNA7 gene that includes exons 5 - 10 and consider-
able sequence downstream. Evidence from multiple
studies supports a broad region of genetic linkage around
the marker D15S1360 [293].
Autism and mental retardation show high rates of co-
morbidity and potentially share genetic risk factors. A
rare approximately 2 Mb microdeletion involving chro-
mosome band 15q13.3 was detected in a multiplex au-
tism family. This genomic loss lies between distal break
points of the Prader-Willi/Angelman syndrome locus and
was first described in association with mental retardation
and epilepsy. Together with recent studies that have also
implicated this genomic imbalance in SCZ, this CNV
shows considerable phenotypic variability [294].
Deletions and reciprocal duplications of the chromo-
some 16p13.1 region have been reported in several cases
of autism, mental retardation and SCZ. Ingason et al.
[295] found a threefold excess of duplications and dele-
tions in SCZ cases compared with controls, with duplica-
tions present in 0.30% of cases vs 0.09% of controls and
deletions in 0.12% of cases and 0.04% of controls. The
region can be divided into three intervals defined by
flanking low copy repeats. Duplications spanning inter-
vals I and II showed the most significant association with
SCZ. The age of onset in duplication and deletion carri-
ers among cases ranged from 12 to 35 years, and the
majority were males with a family history of psychiatric
disorders. Candidate genes in the region include NTAN1
and NDE1.
Velocardiofacial syndrome, now known as 22q11.2
deletion syndrome (22qDS), is estimated to affect more
than 700 children born in the United States each year.
Some clinical studies have found increased rates of SCZ
in adults with 22qDS. The psychiatric disorders most
commonly reported in children and adolescents with
22qDS have been attention-deficit hyperactivity disorder,
oppositional defiant disorder, anxiety disorders, and ma-
jor depression. Psychotic symptoms have been observed
in 14% to 28% of children with 22qDS [296]. Chromo-
some 22q11.2 deletion syndrome (22q11DS) is associ-
ated with cognitive deficits and morphometric brain ab-
normalities in childhood and a markedly elevated risk of
SCZ in adolescence/early adulthood. Children with
22q11DS demonstrate gray matter reductions in multiple
brain regions that are thought to be relevant to SCZ. The
correlation of these volumetric reductions with poor
neurocognition indicates that these brain regions may
mediate higher neurocognitive functions implicated in
SCZ [297]. Recurrent or overlapping CNVs were found
in cases at 39.3% of selected loci. The collective fre-
quency of CNVs at these loci is significantly increased in
cases with autism, in cases with SCZ, and in cases with
mental retardation compared with controls in France.
Individual significance was reached for the association
between autism and a 350-kilobase deletion located at
22q11 and spanning the PRODH and DGCR6 genes
[298]. The 22q11 deletion (or DiGeorge) syndrome
(22q11DS), the result of a 1.5- to 3-megabase hemizy-
gous deletion on human chromosome 22, results in dra-
matically increased susceptibility for “diseases of corti-
cal connectivity” thought to arise during development,
including SCZ and autism. Diminished dosage of the
genes deleted in the 1.5-megabase 22q11 minimal critical
deleted region in a mouse model of 22q11DS specifically
compromises neurogenesis and subsequent differentia-
tion in the cerebral cortex [299]. There is overwhelming
evidence that children and adults with 22q11.2 deletion
syndrome (22q11.2DS) have a characteristic behavioral
phenotype. In particular, there is a growing body of evi-
dence that indicates an unequivocal association between
22q11.2DS and SCZ, especially in adulthood. Deletion
of 22q11.2 is the third highest risk for the development
of SCZ, with a greater risk only conferred by being the
child of two parents with SCZ or the monozygotic
co-twin of an affected individual. Both linkage and asso-
ciation studies of people with SCZ have implicated sev-
eral susceptibility genes, of which three are in the
22q11.2 region: catechol-o-methyltransferase (COMT),
proline dehydrogenase (PRODH), and Gnb1L. In addi-
tion, variation in Gnb1L is associated with the presence
of psychosis in males with 22q11.2DS. In mouse models
of 22q11.2DS, haploinsufficiency of Tbx1 and Gnb1L is
associated with reduced prepulse inhibition, a SCZ
endophenotype [300].
Initial studies of genome-wide trinucleotide repeats
using the repeat expansion detection technique suggested
possible association of large CAG/CTG repeat tracts
with SCZ and bipolar affective disorder [301]. Tandem
repeats, particularly with long (>50 bp) repeat units, are a
relatively common yet underexplored type of CNV that
may significantly contribute to human genomic variation
and disease risk. A bacterial artificial chromosome-based
array comparative genomic hybridization (aCGH) plat-
form screen detected an apparent deletion on 5p15.1 in
two probands, caused by the presence in each proband of
two low copy number (short) alleles of a tandem repeat
that ranges in length from fewer than 10 to greater than
50 3.4 kb units in the population examined. Short alleles
partially segregate with SCZ in a small number of fami-
lies [302].

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 110
Significant familiality of incongruent psychosis was
observed in patients with bipolar I disorder or schizoaf-
fective disorder, bipolar type. Covariate linkage analysis
provided three regions with genome-wide suggestive
evidence for linkage on chromosomes 1q32.3, 7p13 and
20q13.31 in a European sample [303].
The advent of molecular cytogenetic technologies has
altered the means by which new microdeletion syn-
dromes are identified. Whereas the cytogenetic basis of
microdeletion syndromes has traditionally depended on
the serendipitous ascertainment of a patient with estab-
lished clinical features and a chromosomal rearrange-
ment visible by G-banding, comparative genomic hy-
bridization using microarrays has enabled the identifica-
tion of novel, recurrent imbalances in patients with men-
tal retardation and apparently nonspecific features.
Compared with the “phenotype-first” approach of tradi-
tional cytogenetics, array-based comparative genomic
hybridization has enabled the detection of novel genomic
disorders using a “genotype-first” approach. An illustra-
tive example was the characterization of a novel mi-
crodeletion syndrome of 1q41q42. In a sample of over
10,000 patients with developmental disabilities, 7 cases
were found with de novo deletions of 1q41q42. The
smallest region of overlap is 1.17 Mb and encompasses
five genes, including DISP1, a gene involved in the sonic
hedgehog signaling pathway, the deletion of which has
been implicated in holoprosencephaly in mice. Although
none of these patients showed frank holoprosencephaly,
many had other midline defects (cleft palate, diaphrag-
matic hernia), seizures, and mental retardation or devel-
opmental delay. Dysmorphic features are present in all
patients at varying degrees. This new microdeletion syn-
drome with its variable clinical presentation may be re-
sponsible for a proportion of Fryns syndrome patients
and adds to the increasing number of new syndromes
identified with array-based comparative genomic hy-
bridization [304].
Some other novel microdeletion syndromes have been
detected with array-comparative genomic hybridization
(array CGH), including the 17q21.31 deletion and
17q21.31 duplication syndromes, 15q13.3 deletion syn-
drome, 16p11.2 deletion syndrome, 15q24 deletion syn-
drome, 1q41q42 deletion syndrome, 2p15p16.1 deletion
syndrome and 9q22.3 deletion syndrome [305].
Autism spectrum disorders (ASDs) are childhood
neurodevelopmental disorders with complex genetic ori-
gins. Previous studies focusing on candidate genes or
genomic regions have identified several CNVs associ-
ated with an increased risk of ASDs. A whole-genome
CNV study on a cohort of 859 ASD cases and 1409
healthy children of European ancestry genotyped with
approximately 550000 SNP markers, besides previously
reported ASD candidate genes such as NRXN1 and
CNTN4, several new susceptibility genes encoding neu-
ronal cell-adhesion molecules, including NLGN1 and
ASTN2, were enriched with CNVs in ASD cases com-
pared to controls. CNVs within or surrounding genes
involved in the ubiquitin pathways, including UBE3A,
PARK2, RFWD2 and FBXO40, were affected by CNVs
not observed in controls. Duplications 55 kb upstream of
complementary DNA AK123120 were also identified.
Genes involved in neuronal cell-adhesion or ubiquitin
degradation that belong to important gene networks ex-
pressed within the CNS may contribute to the genetic
susceptibility of ASD [306].
In another genome-wide CNVs study, through priori-
tization of exonic deletions (eDels), exonic duplications
(eDups), and whole gene duplication events (gDups),
over 150 loci harboring rare variants in multiple unre-
lated probands, but no controls, were identified in ASDs.
Rare variants at known loci, including exonic deletions at
NRXN1 and whole gene duplications encompassing
UBE3A and several other genes in the 15q11-q13 region,
were observed in these analyses. Strong support was
likewise observed for previously unreported genes such
as BZRAP1, an adaptor molecule known to regulate syn-
aptic transmission, with eDels or eDups observed in
twelve unrelated cases but no controls. MDGA2 was
observed to be case-specific, and the encoded protein
showed an unexpectedly high similarity to Contactin 4,
which has also been linked to disease [307].
Linkage studies have identified several replicated sus-
ceptibility loci for ASDs, including 2q24-2q31, 7q, and
17q11-17q21. Association studies and mutation analysis
of candidate genes have implicated the synaptic genes
NRXN1, NLGN3, NLGN4, SHANK3, and CNTNAP2
in ASDs. Traditional cytogenetic approaches highlight
the high frequency of large chromosomal abnormalities
(3% - 7% of patients), including the most frequently-
observed maternal 15q11-13 duplications (1% - 3% of
patients) [308].
Cornelia de Lange syndrome (CdLS) is a multisystem
congenital anomaly disorder. Heterozygous point muta-
tions in three genes (NIPBL, SMC3 and SMC1A), en-
coding components of the sister chromatid cohesion ap-
paratus, are responsible for approximately 50% - 60% of
CdLS cases. Recent studies have revealed a high degree
of genomic rearrangements (deletions and duplications)
in the human genome, which result in gene CNVs. Du-
plications on chromosomes 5 or X have been identified
in CdLS using genome-wide array comparative genomic
hybridization. The duplicated regions contain either the
NIPBL or the SMC1A genes. Junction sequence analyses
revealed the involvement of three genomic rearrange-
ment mechanisms. The patients share some common
features including mental retardation, developmental
delay, sleep abnormalities, and craniofacial and limb

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 111
defects. The systems affected are the same as in CdLS,
but clinical manifestations are distinct from CdLS; par-
ticularly the absence of the CdLS facial gestalt. The re-
sults confirm the notion that duplication CNV of genes
can be a common mechanism for human genetic diseases
[309].
The rate of de novo mutations is of relevance to evolu-
tion and disease. Kong et al. [310] conducted a study of
genome-wide mutation rates by sequencing the entire
genomes of 78 Icelandic parent-offspring trios at high
coverage, and showed that with an average father’s age
of 29.7, the average de novo mutation rate is 1.20 × 10−8
per nucleotide per generation. The diversity in mutation
rate of single nucleotide polymorphisms is dominated by
the age of the father at conception of the child. The effect
is an increase of about two mutations per year with pa-
ternal mutations doubling every 16.5 years. According to
Steffanson’s group [310], father’s age is estimated to
explain nearly all of the remaining variation in the de
novo mutation counts with potential repercussion on the
risk of diseases such as SCZ and autism.
3.4. SNPs in Human miRNA Genes
MicroRNAs (miRNAs) are 21 - 25-nucleotide-long, non-
coding RNAs involved in translational regulation. Most
miRNAs derive from a two-step sequential processing:
the generation of pre-miRNA from pri-miRNA by the
Drosha/DGCR8 complex in the nucleus, and the genera-
tion of mature miRNAs from pre-miRNAs by the
Dicer/TRBP complex in the cytoplasm. Sequence varia-
tion around the processing sites, and sequence variations
in the mature miRNA, especially the seed sequence, may
have profound effects on miRNA biogenesis and func-
tion. Naturally occurring SNPs can impair or enhance
miRNA processing as well as alter the sites of processing.
Since miRNAs are small functional units, single base
changes in both the precursor elements as well as the
mature miRNA sequence may drive the evolution of new
microRNAs by altering their biological function. At least
24 human X-linked miRNA variants with potential in-
fluence in SCZ have been identified [311]. Individual
microRNAs (miRNAs) affect moderate downregulation
of gene expression. Components required for miRNA
processing and/or function have also been implicated in
X-linked mental retardation, neurological and neoplastic
diseases, pointing to the wide-ranging involvement of
miRNAs in disease. To explore the role of miRNAs in
SCZ, 59 microRNA genes on the X-chromosome were
amplified and sequenced in males with and without SCZ
spectrum disorders to test the hypothesis that ultra-rare
mutations in microRNA collectively contribute to the
risk of SCZ. Feng et al. [312] provided the first associa-
tion of microRNA gene dysfunction with SCZ. Eight
ultra-rare variants in the precursor or mature miRNA
were identified in eight distinct miRNA genes in 4% of
analyzed males with SCZ. One ultra-rare variant was
identified in a control sample. These variants were not
found in an additional 7197 control X-chromosomes.
Functional analyses of ectopically expressed copies of
the variant miRNA precursors demonstrate loss of func-
tion, gain of function or altered expression levels. These
findings suggest that microRNA mutations can contrib-
ute to SCZ [312].
At least one third of known miRNA genes are ex-
pressed in the brain. Mutations disrupting MECP2 pro-
tein lead to abnormal development of the brain and re-
sulting behavior. MiR-130b expressed in the brain and
potentially targeting MECP2 is located in the susceptibil-
ity locus for SCZ (22q11). Screening for mutations has
identified a population polymorphism in the 5-upstream
miR-130b gene region containing DNA elements for
putative transcription factors. Genetic association analy-
sis of 300 schizophrenics and 316 controls revealed no
statistically significant association of any of the miR-
130b allelic variants with SCZ [313].
For posttranscriptional gene silencing, one strand of
the miRNA is used to guide components of the RNA
interference machinery, including Argonaute 2, to mes-
senger RNAs (mRNAs) with complementary sequences.
Targeted mRNAs are either cleaved by the endonuclease
Argonaute 2, or protein synthesis is blocked by a specific
mechanism. Genes encoding miRNAs are transcribed as
long primary miRNAs (pri-miRNAs) that are sequen-
tially processed by components of the nucleus and cyto-
plasm to yield a mature, approx 22-nucleotide (nt)-long
miRNA. Two members of the ribonuclease (RNase) III
endonuclease protein family, Drosha and Dicer, have
been implicated in this two-step processing. Several pro-
teins are required for the initial nuclear processing of
pri-miRNAs to the approx 60- to 70-nt stem-loop inter-
mediates known as precursor miRNAs (pre-miRNAs). A
protein complex, termed Microprocessor by Gregory et
al. [314], is necessary and sufficient for processing
pri-miRNA to premiRNAs. The Microprocessor complex
comprises Drosha and the double-stranded RNA-binding
protein DiGeorge syndrome critical region 8 gene
(DGCR8), which is deleted in DiGeorge syndrome [314].
Identification of known miRNA targets on all human
genes indicates that miRNA-346 targets SCZ suscept-
ibility genes listed in the Schizophrenia Gene database
twice as frequently as expected, relative to other genes in
the genome. The gene encoding this miRNA, miR-346,
is located in intron 2 of the glutamate receptor ionotropic
delta 1 (GRID1) gene, which has been previously impli-
cated in SCZ susceptibility. Expression of both miR-346
and GRID1 is lower in SCZ patients than in normal con-
trols; however, the expression of miR-346 and GRID1 is
less correlated in SCZ patients than in bipolar patients or

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 112
in normal controls [315]. Cummings et al. [316] geno-
typed 821 patients with confirmed DSM-IV diagnoses of
SCZ, bipolar affective disorder I and schizoaffective dis-
order for the risk SNP (rs1625579) of a micro-RNA,
MIR-137, and found that carriers of the risk allele had
lower scores for an OPCRIT-derived positive symptom
factor and lower scores on a lifetime measure of psycho-
sis incongruity. Risk allele carriers also had more cogni-
tive deficits involving episodic memory and attentional
control. The MIR-137 risk variant may be associated
with a specific subgroup of psychosis patients.
3.5. Epigenetics
Despite the promising results obtained with structural
and functional genomic procedures to identify associa-
tions with disease pathogenesis and potential drug targets
in CNS disorders, it must be kept in mind that allelic
mRNA expression is affected by genetic and epigenetic
events, both with the potential to modulate neurotrans-
mitter tone in the CNS [317]. Epigenetics is the study of
how the environment can affect the genome of the indi-
vidual during its development as well as the development
of its descendants, all without changing the DNA se-
quence, but inducing modifications in gene expression
through DNA methylation-demethylation or through
modification of histones by processes of methylation,
deacetylation, and phosphorylation [318]. DNA methyla-
tion is an epigenetic mechanism in which the methyl
group is covalently coupled to the C5 position of the
cytosine residue of CpG dinucleotides, generally leading
to gene silencing. DNA methylation is catalyzed by a
group of enzymes known as DNA methyltransferases
(DNMT). DNA methylation changes only happen during
DNA replication to maintain methylation patterns on
hemimethylated DNA or establish new methylation.
DNMT expression generally decreases after cell division,
but significant levels of DNMTs are present in postmi-
totic neurons. There is evidence that DNA methylation
correlates with some neuropsychiatric disorders, influ-
ences neural development, plasticity, learning, and
memory, and is potentially reversible at certain genomic
loci. This epigenetic mechanism of gene regulation gives
support to a maintenance role of DNMT to prevent active
demethylation in postmitotic neurons [319]. Genomic
and epigenetic changes can affect complex cognitive
functions, including learning and memory, and are
causative in several developmental and psychiatric dis-
orders affecting language, social functioning and IQ
[320]. DNA methylation and histone deacetylation are
two major epigenetic modifications that contribute to the
stability of gene expression states. Perturbing DNA me-
thylation, or disrupting the downstream response to DNA
methylation-methyl-CpG-binding domain proteins (MBDs)
and histone deacetylases (HDACs) by genetic or phar-
macological means, has revealed a critical requirement
for epigenetic regulation in brain development, learning,
and mature nervous system stability, and has identified
the first distinct gene sets that are epigenetically regu-
lated within the nervous system [321].
Epigenetic mechanisms such as DNA methylation and
modifications to histone proteins regulate high-order
DNA structure and gene expression. Aberrant epigenetic
mechanisms are involved in different CNS disorders
(Rett syndrome, mental retardation disorders, alpha-tha-
lassemia/mental retardation X-linked syndrome, Rubin-
stein-Taybi syndrome, Coffin-Lowry syndrome, Alz-
heimer’s disease, Parkinson’s disease, Huntington’s dis-
ease, multiple sclerosis, epilepsy, amyotrophic lateral
sclerosis) and also probably in mental disorders [322].
More than 150 post-translation modifications of his-
tones have been reported, including methylations, acety-
lations, ubiquitinations, SUMOylations and phosphoryla-
tions. A macro-molecular complex, called ECREM for
“Epigenetic Code REplication Machinery”, has been
proposed as a potential mechanism involved in the in-
heritance of the epigenetic code. The composition of
ECREM may vary in a spatio-temporal manner accord-
ing to the chromatin state, the cell phenotype and the
development stage. Members of ECREM, responsible for
the epigenetic code inheritance, include enzymes in-
volved in DNA methylation and histone post-transla-
tional modifications. Some of them, such as DNA me-
thyltransferases (DNMTs), histone acetyltransferases
(HATs) and histone deacetylases (HDACS, including
sirtuins), have been found to be deregulated in several
types of pathologies and are already targeted by inhibi-
tors [323].
Epigenetic phenomena cannot be neglected in the
pathogenesis and pharmacogenomics of CNS disorders.
Studies in cancer research have demonstrated the anti-
neoplastic effects of the DNA methylation inhibitor hy-
dralazine and the histone deacetylase inhibitor valproic
acid, of current use in epilepsy [324]. Novel effects of
some pleiotropic drugs with activity on the CNS have to
be explored to understand in full their mechanisms of
action and adjust their dosages for new indications. Both
hyper- and hypo-DNA methylation changes of the regu-
latory regions play critical roles in defining the altered
functionality of genes (MB-COMT, MAOA, DAT1, TH,
DRD1, DRD2, RELN, BDNF) in major psychiatric dis-
orders, such as SCZ and BD [325].
Histone deacetylases (HDACs), enzymes that affect
the acetylation status of histones and other important
cellular proteins, have been recognized as potentially
useful therapeutic targets for a broad range of human
disorders. Pharmacological manipulations using small-
molecule HDAC inhibitors, which may restore trans-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 113
criptional balance to neurons, modulate cytoskeletal
function, affect immune responses and enhance protein
degradation pathways, have been beneficial in various
experimental models of brain diseases [326].
Recent advances in SCZ research indicate that the tel-
encephalic gamma-aminobutyric acid (GABA)ergic
neurotransmission deficit associated with this psychiatric
disorder is probably mediated by the hypermethylation of
the glutamic acid decarboxylase 67 (GAD67), reelin and
other GABAergic promoters. A pharmacological strategy
to reduce the hypermethylation of GABAergic promoters
is to induce a DNA-cytosine demethylation by altering
the chromatin remodeling with valproate (VPA). When
co-administered with VPA, the clinical efficacy of atypi-
cal antipsychotics is enhanced. VPA facilitates chromatin
remodeling when it is associated with clozapine or
sulpiride but not with haloperidol or olanzapine [327].
This remodeling might contribute to reelin- and GAD67-
promoter demethylation and might reverse the GABAer-
gic gene-expression downregulation associated with SCZ
morbidity [328,329].
Reduction of prefrontal cortex glutamic acid decar-
boxylase (GAD67) and reelin (mRNAs and proteins)
expression is the most consistent finding reported by
several studies of post-mortem SCZ brains. The reduced
GAD67 and reelin expression in cortical GABAergic
interneurons of SCZ brains is the consequence of an
epigenetic hypermethylation of RELN and GAD67 pro-
moters very likely mediated by the overexpression of
DNA methyltransferase 1 in cortical GABAergic in-
terneurons. RELN and GAD67 promoters express an in-
creased recruitment of methyl-CpG binding domain pro-
teins. The histone deacetylase inhibitor valproate, which
increases acetylated histone content in cortical GABAer-
gic interneurons, also prevents MET-induced RELN
promoter hypermethylation and reduces the methyl-CpG
binding domain protein binding to RELN and GAD67
promoters. DNA hypermethylation and the associated
chromatin remodeling may be critically important in me-
diating the epigenetic down-regulation of reelin and
GAD67 expression detected in cortical GABAergic in-
terneurons of SCZ patients [330,331].
Novel strategies in psychiatric epigenetics have been
developed. With two novel approaches, it has been ob-
served that valproic acid induced a 383% increase in
GAD67 mRNA, an 89% increase in total acetylated his-
tone 3 (H3K9, K14ac) levels, and a 482% increase in
H3K9,K14ac attachment to the GAD67 promoter.
Trichostatin A (TSA) induced comparable changes on all
measures. Bipolar patients had significantly higher base-
line levels of H3K9, K14ac compared to patients with
SCZ. Subjects with clinically relevant serum levels of
valproic acid (>65 μg/mL) showed a significant increase
in mRNA expression. Separate approaches for examining
chromatin remodeling in real clinical time provide evi-
dence for differential epigenetic events in cultured lym-
phocytes isolated from patients with SCZ and bipolar
depression [332].
Li et al. [333] examined associations of structural mu-
tability with germline DNA methylation and with
non-allelic homologous recombination (NAHR) medi-
ated by low-copy repeats (LCRs). Combined evidence
from four human sperm methylome maps, human ge-
nome evolution, structural polymorphisms in the human
population, and previous genomic and disease studies
consistently points to a strong association of germline
hypomethylation and genomic instability. Methylation
deserts, the ~1% fraction of the human genome with the
lowest methylation in the germline, show a tenfold en-
richment for structural rearrangements that occurred in
the human genome since the branching of chimpanzee
and are highly enriched for fast-evolving loci that regu-
late tissue-specific gene expression. Analysis of copy
number variants (CNVs) from 400 human samples indi-
cates that association of structural mutability with germ-
line hypomethylation is comparable in magnitude to the
association of structural mutability with LCR-mediated
NAHR. Rare CNVs occurring in the genomes of indi-
viduals diagnosed with SCZ, bipolar disorder, and de-
velopmental delay and de novo CNVs occurring in those
diagnosed with autism are significantly more concen-
trated within hypomethylated regions.
3.6. Mitochondrial DNA Mutations
Mitochondria provide most of the energy for brain cells
by the process of oxidative phosphorylation. Mito-
chondrial oxidative phosphorylation is the major ATP-
producing pathway, which supplies more than 95% of the
total energy requirement in the cells. Damage to the mi-
tochondrial electron transport chain has been suggested
to be an important factor in the pathogenesis of a range
of psychiatric disorders. Tissues with high energy de-
mands, such as the brain, contain a large number of mi-
tochondria, being therefore more susceptible to reduction
of the aerobic metabolism. Mitochondrial abnormalities
and deficiencies in oxidative phosphorylation have been
reported in individuals with SCZ, BD, and major depres-
sive disorder (MDD) in transcriptomic, proteomic, and
metabolomic studies. The evidence includes impaired
energy metabolism in the brain, detected using results of
magnetic resonance spectroscopy, electron microscopy,
co-morbidity with mitochondrial diseases, the effects of
psychotropics on mitochondria, increased mitochondrial
DNA (mtDNA) deletion in the brain, and association
with mtDNA mutations/polymorphisms or nuclear-en-
coded mitochondrial genes. Alterations of mitochondrial
oxidative phosphorylation in SCZ have been reported in
several brain regions and also in platelets. Abnormal mi-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 114
tochondrial morphology, size and density have all been
reported in the brains of schizophrenic individuals
[334,335]. Several mutations in mtDNA sequence have
been reported in SCZ and BD patients. The rate of syn-
onymous base pair substitutions in the coding regions of
the mtDNA genome is 22% higher in the dorsolateral
prefrontal cortex of individuals with SCZ compared to
controls [336].
Analyses of mitochondria-related genes using DNA
microarray showed significantly increased LARS2 (mi-
tochondrial leucyl-tRNA synthetase) in the post-mortem
prefrontal cortices of patients with BD. LARS2 is a nu-
clear gene encoding the enzyme catalyzing the aminoa-
cylation of mitochondrial tRNA-Leu. A well-studied mi-
tochondrial DNA point mutation, 3243A > G, in the re-
gion of tRNA-LeuUUR, related with MELAS (mitochon-
drial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes), is known to decrease the efficiency
of aminoacylation of tRNA-LeuUUR. The steady state
level of LARS2 was examined in the transmitochondrial
cybrids carrying 3243A > G. LARS2 was upregulated in
the transmitochrondrial cybrids carrying 3243A > G. The
3243A > G was detected in the post-mortem brains of
patients with BD and SCZ, who also showed higher lev-
els of the mutation in their livers and significantly higher
gene expression of LARS2. Upregulation of LARS2 is a
hallmark of 324A > G mutation. The accumulation of
3243A > G mutation in the brain may have a pathophysi-
ologic role in BD and SCZ [337].
A decreased expression of mitochondrial complex I
subunit gene, NDUFV2 at 18p11, in lymphoblastoid cell
lines (LCLs) from Japanese patients with BD, has been
reported. No differences were found in NDUFV2 mRNA
levels in LCLs of Caucasian BD patients compared with
controls [338].
Park et al. [339] characterized Mitofilin, a mitochon-
drial inner membrane protein, as a mediator of the mito-
chondrial function of DISC1. A fraction of DISC1 was
localized to the inside of mitochondria and directly in-
teracts with Mitofilin. A reduction in DISC1 function
induced mitochondrial dysfunction, evidenced by de-
creased mitochondrial NADH dehydrogenase activities,
reduced cellular ATP contents, and perturbed mitochon-
drial Ca2+ dynamics. Deficiencies in DISC1 and Mitofilin
induced a reduction in mitochondrial monoamine oxi-
dase-A activity. The mitochondrial dysfunctions evoked
by the deficiency of DISC1 were partially phenocopied
by an overexpression of truncated DISC1 that is associ-
ated with SCZ in humans. DISC1 deficiencies induced
the ubiquitination of Mitofilin, suggesting that DISC1 is
critical for the stability of Mitofilin. The mitochondrial
dysfunction induced by DISC1 deficiency was partially
reversed by coexpression of Mitofilin, confirming a
functional link between DISC1 and Mitofilin for the
normal mitochondrial function. DISC1 may play essen-
tial roles for mitochondrial function in collaboration with
the mitochondrial interacting partner Mitofilin.
3.7. Genotype-Phenotype Correlations,
Transcriptomics, Proteomics, and
Metabolomics
Genotype-phenotype correlations represent a central is-
sue in functional genomics to validate the impact of ge-
nomic factors on disease pathogenesis and phenotypic
expression of disease-related genes as well as in phar-
macogenetics and pharmacogenomics [4]. Phenomics,
the systematic study of phenotypes on a genome-wide
scale, comprises a rate-limiting step on the road to ge-
nomic discovery [340]. Novel strategies to assess geno-
type-phenotype correlates have been developed. For in-
stance, by using the parallel independent component
analysis (para-ICA) of Liu to analyze a multimodal data
set in which each subject was characterized on 24 dif-
ferent SNP markers spanning multiple risk genes previ-
ously associated with SCZ, Meda et al. [341] detected
three fMRI components significantly correlated with two
distinct gene components. The fMRI components, along
with their significant genetic profile (dominant SNP)
correlations were as follows: 1) Inferior frontal-anterior/
posterior cingulate-thalamus-caudate with SNPs from
BDNF and DAT, 2) superior/middle temporal gyrus-
cingulate-premotor with SLC6A4_PR and SLC6A4_PR_
AG (serotonin transporter promoter; 5HTTLPR), and 3)
default mode-fronto-temporal gyrus with BDNF and
DAT. These results reveal the effect/influence of specific
interactions, between SCZ risk genes on imaging endo-
phenotypes representing attention/working memory and
goal-directed related brain function, thus establishing a
useful methodology to probe multivariate genotype-
phenotype relationships [341].
Bergen et al. [342] tested four genes [phenylalanine
hydroxylase (PAH), the serotonin transporter (SLC6A4),
monoamine oxidase B (MAOB), and the gamma-ami-
nobutyric acid A receptor beta-3 subunit (GABRB3)] for
their impact on five SCZ symptom factors: delusions,
hallucinations, mania, depression, and negative symp-
toms. The PAH 232 bp microsatellite allele demonstrated
significant association with the delusions factor, and a
significant association between the GABRB3 191 bp
allele and the hallucinations factor was also detected
[342].
Transcriptomics and gene expression studies are also
helping to elucidate the role of the prefrontal cortex in
SCZ and affective disorders. Owing to reciprocal con-
nectivity, the thalamic nuclei and their cortical fields act
as functional units. Chu et al. [343] screened the expres-
sion of the entire human genome of neurons harvested by
laser-capture microdissection (LCM) from the thalamic

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 115
primary relay to dorsolateral prefrontal cortex in three
psychiatric disease states as compared with controls.
Microarray analysis of gene expression showed the larg-
est number of dysregulated genes in SCZ, followed by
major depression and D8, respectively. Significantly,
IGF1-mTOR-, AKT-, RAS-, VEGF-, Wnt- and immune-
related signaling, eIF2- and proteasome-related genes
were unique to SCZ. Vitamin D receptor and calcium
signaling pathway were unique to BD. AKAP95 pathway
and pantothenate and CoA biosynthesis were unique to
major depression [343].
Studies on the human CNS transcriptome suggest
changes in pro-inflammatory pathways and myelination
in SCZ, whereas changes in the proteome suggest that
pathways involved in energy and metabolism may be
particularly stressed. There appear to be complex
changes in the expression of proposed candidate genes
for SCZ such as NRG1, DISC1, RGS4 and DTNB1, and
there are continued reports of alterations in central
gamma-aminobutyric acidergic, dopaminergic, glutama-
tergic and cholinergic pathways in patients with the dis-
order. Data on epigenetic mechanisms and transcriptome
regulation suggest that at least some changes in gene
expression may be due to changes in levels of gene pro-
moter methylation or microRNAs in the CNS of patients
with SCZ [344].
SCZ is likely to be a consequence of DNA alterations
that, together with environmental factors, will lead to
protein expression differences and the ultimate establish-
ment of the illness. The superior temporal gyrus is im-
plicated in SCZ and executes functions such as the proc-
essing of speech, language skills and sound processing.
Proteomics studies in the left posterior superior temporal
gyrus (Wernicke’s area - BA22p) revealed 11 downregu-
lated and 14 upregulated proteins, most of them related
to energy metabolism. Whereas many of the identified
proteins have been previously implicated in SCZ, such as
fructose-bisphosphate aldolase C, creatine kinase and
neuron-specific enolase, new putative disease markers
were also identified such as dihydrolipoyl dehydrogenase,
tropomyosin 3, breast cancer metastasis-suppressor 1,
heterogeneous nuclear ribonucleoproteins C1/C2 and
phosphate carrier protein, mitochondrial precursor [345].
Genome-wide expression analysis of peripheral blood
identified candidate biomarkers for SCZ. Using Affy-
metrix micoarrays, Kuzman et al. [346] identified sig-
nificantly altered expression of 180 gene probes in psy-
chotic patients compared to controls. The following
genes were significantly altered in patients: glucose
transporter, SLC2A3 and actin assembly factor DAAM2
were increased, whereas translation, zinc metallopepti-
dase, neurolysin 1 and myosin C were significantly de-
creased. DAAM2 polymorphic variants have been found
significantly associated with SCZ [346].
The repertoire of biochemicals present in cells, tissue,
and body fluids is known as the metabolome. State of the
art metabolomic analytical platforms and informatics
tools are being used to map potential biomarkers for
CNS disorders. Early findings from metabolomic studies
may help to identify promising biomarkers for SCZ and
many other neuropsychiatric disorders [347].
4. PHARMACOGENOMICS OF
ANTIPSYCHOTIC DRUGS
4.1. Aripiprazole
Aripiprazole is an arylpiperazine atypical antipsychotic
with full agonist activity for 5-HT1A, 5-HT1B, 5-HT1D,
5-HT6, 5-HT receptors, acting also as a partial agonist of
D2 and 5-HT1A receptors and antagonist of the 5-HT2A
receptor. Aripiprazole is a major substrate of CYP2D6
and CYP3A4. Caution and personalized dose adjustment
should be made in patients with the following genotypes:
ADRA1A (Arg347Cys), CYP2D6 (CYP2D6*3,
CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7,
CYP2D6*8, CYP2D6*10, CYP2D6*17, CYP2D6*1xN),
CYP3A4 and CYP3A5 (CYP3A4*1, CYP3A4*1B,
CYP3A4*2, CYP3A4*3, CYP3A4*4, CYP3A4*5,
CYP3A4*6, CYP3A4*8, CYP3A4*11, CYP3A4*12,
CYP3A4*13, CYP3A4*15, CYP3A4*17, CYP3A4*18,
CYP3A4*19, CYP3A5*3), DRD2 (TaqIA RFLP
(rs1800497, ANKK1), TaqIB (rs1079597), rs6277),
DRD3 (Ser9Gly), HTR2A (His452Tyr, His368Tyr,
Ile197Val, Ile113Val, Ala447Val, Ala363Val, Thr25Asn,
A-1438G (rs6311), T102C (rs6313)), HTR2C (Cys23Ser,
−759C/T), and also in ABCB1 and HTR1A mutants [25]
(Table 2).
4.2. Benperidol
Benperidol is a butyrophenone antipsychotic which blocks
postsynaptic mesolimbic dopaminergic D1 and D2 recep-
tors. Genes potentially involved in efficacy and safety
might be DRD1 and DRD2 [25] (Table 2).
4.3. Bromperidol
Bromperidol is a butyrophenone with antagonistic ac-
tivity on D2 receptors and a moderate antagonistic activ-
ity on serotonin 5-HT2 receptors. Bromperidol is a major
substrate of CYP3A4, a minor substrate of CYP2D6, a
substrate of several UGTs, and a moderate inhibitor of
CYP2D6. ABCB1 (C3435T and G2677T/A), DRD2
(Taq IA RFLP and rs1800497, ANKK1), and HTR2 vari-
ants may influence its pharmacokinetics and pharmaco-
dynamics [25] (Table 2).
4.4. Chlorpromazine
Chlorpromazine is an aliphatic phenothiazine antipsy-

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 116
chotic which blocks postsynaptic mesolimbic dopa-
minergic D1 and D2 receptors, has a strong anticholiner-
gic effect, weakly blocks ganglionic, antihistaminic and
antiserotonergic receptors, strongly blocks α-adrenergic
receptors, and behaves as an inverse agonist of 5-HT6
and 5-HT7 receptors and as an antagonist of 5-HT1A and
5-HT2c receptors. Chlorpromazine is a major substrate of
CYP2D6, a minor substrate of CYP1A2 and CYP3A4,
and a substrate of UGT1A3 and UGT1A4. This neuro-
leptic strongly inhibits CYP2D6 and weakly CYP2E1
and DAO. Caution and personalized dose adjustment
should be made in patients with the following genotypes:
ACACA (rs4072032,rs2229416 (Gln526His), rs1266175,
rs12453407, rs9906543), BDNF ((GT)n), CYP1A2
(C734A, G-2964A), CYP2D6 (CYP2D6*3, CYP2D6*4,
CYP2D6*5, CYP2D6*6, CYP2D6*7, CYP2D6*8,
CYP2D6*10, CYP2D6*17, CYP2D6*1xN), DRD2
(−141C Ins/Del) (rs1799732) TaqIA RFLP (rs1800497,
ANKK1), TaqIB (rs1079597), TaqID (rs1800498),
(Ser311Cys, rs6276 and rs6277), DRD3 (Ser9Gly),
HTR2C (−759C/T in the promoter region), LEP
(–2548G/A), and NPY (rs1468271). ABCB1, CFTR,
CYP2A6, CYP2C9, CYP2C19, CYP2E1, CYP3A4,
DAO, FABP1, FMO1, UGT1A3, and UGT1A4 variants
may also influence its pharmacokinetics and pharma-
codynamics [25] (Table 2).
4.5. Clozapine
Clozapine is a dibenzodiazepine atypical antipsychotic
which acts as an antagonist of histamine H1, cholinergic
and α1-adrenergic receptors, an antagonist of 5-HT1A and
5-HT2B receptors, a full agonist of 5-HT1A, 5-HT1B,
5-HT1D, and 5-HT1F receptors, and an inverse agonist of
5-HT6 and 5-HT7 receptors. Clozapine is a major sub-
strate of ABCB1, CYP1A2 and CYP3A4, a minor sub-
strate of CYP2A6, CYP2C8, CYP2C9, CYP2C19 and
CYP2D6, and also substrate of FMO3, UGT1A3 and
UGT1A4. This atypical antipsychotic moderately inhibits
CYP2C9, CYP2C19 and CYP2D6, and weakly inhibits
CYP1A2, CYP2E1 and CYP3A4. Caution and personal-
ized dose adjustment should be made in patients with the
following genotypes: APOA5 (−1131C > T, Ser19Trp),
APOC3 (C1100T), APOD (rs7659), CYP1A2 (C734A,
G-2964A, C1545T), DRD1 (rs4532, rs265976), DRD2
(TaqIA RFLP (rs1800497, ANKK1), Taq1B (rs1079597),
rs1125394), DRD3 (Ser9Gly), DTNBP1 (rs1018381,
rs760761, rs2619539, rs742105, Diplotype ACCCTC/
GTTGCC, rs742106), GNB3 (Ser275Ser), HTR1F
(C267T), HTR2A (His452Tyr, His368Tyr, Ile197Val,
Ile113Val, Ala447Val, Ala363Val, Thr25Asn), HTR2C
(Cys23Ser), TNF (−308G > A), and UGT1A4 (Leu48Val,
Leu150Leu, 43fcX22). Other polymorphic variants in the
ABCB1, CNR1, CYP2A6, CYP2D6, CYP2C8, CYP2C9,
CYP2C19, CYP2E1, CYP3A4, DRD4, FABP1, FMO3,
GSK3B, HTR3A, HRH1, HTR6, LPL, NRXN1, RGS2,
and UGT1A3 genes may also influence its pharmacoki-
netics and pharmacodynamics [25] (Table 2).
4.6. Droperidol
Droperidol is a butyrophenone which blocks dopami-
nergic and α-adrenergic receptors. This atypical antipsy-
chotic is a major substrate of CYP2C9, CYP2C19,
CYP2D6, and CYP3A4. ABCC8, ADRA2A, ADRB1,
CHRM2, CYP2C9, CYP2C19, CYP2D6, CYP3A4,
KCNE1, KCNE2, KCNQ1, KCNJ11, and KCNH2 vari-
ants influence its efficacy and safety [25] (Table 2).
4.7. Fluphenazine
Fluphenazine is a piperazine phenothiazine which blocks
postsynaptic mesolimbic dopaminergic D1 and D2 recep-
tors and is an inverse agonist of 5-HT7 receptors, and an
antagonist of 5-HT2A receptors. This typical antipsy-
chotic is a major substrate of CYP2D6; weakly inhibits
CYP1A2, CYP2C9, and CYP2E1; and strongly inhibits
CYP2D6. Caution and personalized dose adjustment
should be made in patients with the following CYP2D6
genotypes: CYP2D6*3, CYP2D6*4, CYP2D6*5,
CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*10,
CYP2D6*17, CYP2D6*1xN. ABCB1, CYP1A2,
CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2E1,
CYP3A4, DRD1, DRD2, HRH1, HTR2A, and HTR7
variants may also affect its pharmacokinetic and phar-
macodynamic properties [25] (Table 2).
4.8. Flupenthixol
Flupenthixol is a thioxanthene with typical antipsychotic
activity by blocking postsynaptic dopaminergic receptors.
DRD1 (Ala229Thr, Arg50Ser, Ser199Ala, Thr37Arg,
Thr37Pro) and DRD2 variants may affect its biopharma-
ceutical properties [25] (Table 2).
4.9. Haloperidol
Haloperidol is a butyrophenone which blocks postsyn-
aptic mesolimbic dopaminergic D1 and D2 receptors, act-
ing also as an antagonist of 5-HT2A and 5-HT2B receptors.
This typical antipsychotic is a major substrate of
CYP2D6 and CYP3A4/5, a minor substrate of CYP1A1,
CYP1A2, CYP2C8, CYP2C9, and CYP2C19, a substrate
of CBR and several UGTs, and a moderate inhibitor of
CYP2D6 and CYP3A4. Caution and personalized dose
adjustment should be made in patients with the following
genotypes: CYP2D6 (CYP2D6*3, CYP2D6*4,
CYP2D6*5, CYP2D6*6, CYP2D6*7, CYP2D6*8,
CYP2D6*10, CYP2D6*17, CYP2D6*1xN), CYP3A4
and CYP3A5 (CYP3A4*1, CYP3A4*1B, CYP3A4*2,
CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6,

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 117
CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13,
CYP3A4*15, CYP3A4*17, CYP3A4*18, CYP3A4*19,
CYP3A5*3), DRD2 (TaqIA RFLP (rs1800497,
ANKK1)), DTNBP1 (rs909706, diplotype
ACCCTC/GCCGCC), HTR2A (A-1438G (rs6311)), and
IL1RN (VNTR (IL1RN*1 and IL1RN*2). ABCB1,
ABCC1, ADRA2A, BDNF, CHRM2, CYP1A2,
CYP2A6, CYP2C9, CYP2C19, DRD1, DRD4, FOS,
GRIN2B, GSK3B, GSTP1, HRH1, HTT, KCNE1,
KCNE2, KCNH2, KCNJ11, and KCNQ1 variants also
affect its neuroleptic properties and side-effects [25]
(Table 2).
4.10. Loxapine
Loxapine is a dibenzoxazepine which blocks postsynap-
tic mesolimbic dopaminergic D1 and D2 receptors and
serotonin 5-HT2 receptors, also acting as an inverse ago-
nist of 5-HT2c and 5-HT6 receptors. This typical antipsy-
chotic is a substrate of UGT1A4, and DRD1, DRD2,
HTR2A, and UGT1A4 variants might be able to modify
its biopharmaceutical properties [25] (Table 2).
4.11. Mesoridazine
Mesoridazine is a phenothiazine with putative dopa-
minergic, cholinergic and adrenergic inhibition. This
typical antipsychotic is a substrate of CYP2J2, and
ADRA1A, DRD2, CHRM2, CYP2J2, KCNE1, KCNE2,
KCNH2, KCNJ11, KCNQ1, SCN5A variants may affect
its pharmacokinetic and pharmacodynamic properties [25]
(Table 2).
4.12. Molindone
Molindone is a dihydroindolone which blocks postsy-
naptic mesolimbic dopaminergic D1 and D2 receptors,
has a strong anticholinergic effect, a weak ganglionic,
antihistaminic and antiserotonergic blocking capacity,
and a strong α-adrenergic blocking activity, also acting as
an antagonist of 5-HT2A receptors. Polymorphic variants
in the ADRA1A, DRD2, DRD3, HRH1, HTR1A,
HTR1E, HTR2A, and HTR2C genes may induce
changes in proteomic byproducts leading to modifica-
tions in the biopharmaceutical properties of this typical
antipsychotic [25] (Table 2).
4.13. Olanzapine
Olanzapine is a thienobenzodiazepine which acts as a
strong antagonist of serotonergic 5-HT2A, 5-HT2C, and
5-HT7 receptors, dopaminergic D1-4 receptors, hista-
minergic H1 receptors, and α1-adrenergic receptors. This
atypical antipsychotic is also an antagonist of 5-HT2A,
5-HT3 and muscarinic M1-5 receptors, a full agonist of
5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F receptors, and an
inverse agonist of 5-HT2c and 5-HT6 receptors. Olanzap-
ine is a major substrate of CYP1A2, CYP2D6 and
UGT1A4, and a weak inhibitor of CYP1A2, CYP2C9,
CYP2C19, CYP2D6, and CYP3A4. Caution and person-
alized dose adjustment should be made in patients with
the following genotypes: ABCB1 (C1236T, G2677T/A,
C3435T), ADRB3 (Arg64Trp), APOA5 (−1131T > C,
Ser19Trp), APOC3 (C1100T), COMT (Val(108/158)
Met), CYP2D6 (CYP2D6*3, CYP2D6*4, CYP2D6*5,
CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*10,
CYP2D6*17, CYP2D6*1xN), DRD2 (TaqIA RFLP
(rs1800497, ANKK1), −141C Ins/Del (rs1799732), −241
A > G, Ser311Cys), DRD3 (Ser9Gly), GNB3
(Ser275Ser), GRM3 (rs6465084, rs274622), HTR2A
(His452Tyr, His368Tyr, Ile197Val, Ile113Val, Ala447Val,
Ala363Val, Thr25Asn, T102C (rs6313)), HTR2C
(Cys23Ser, −759C > T), LEP (rs4731426, −1548G > A),
LEPR (Gln223Arg), RGS2 (rs4606, rs1152746, rs1819741,
rs1933695, rs2179652, rs2746073), SLC6A2 (G1287A,
T-182C), and UGT1A4 (Leu48Val). These genotypes and
other polymorphic variants in the CYP1A2, CYP2C9,
CYP2C19, CYP3A4, DRD4, FMO1, KCNH2, and LPL
genes are determinant for olanzapine-related pharma-
cological properties and/or side-effects [25] (Table 2).
4.14. Paliperidone
Paliperidone is a benzisoxazole which acts as a serotonin
and dopamine receptor antagonist, with high affinity for
α1, D2, H1, and 5-HT2C receptors and low affinity for
muscarinic and 5-HT1A receptors. This atypical antipsy-
chotic is a major substrate of ABCB1, ADH, CYP2D6,
CYP3A4, and several UGTs, and inhibits ABCB1,
CYP2D6, and CYP3A4. Polymorphic variants in the
ABCB1, ADRA1A, ADRA1B, ADRA1D, CYP2D6,
CYP3A4, DRD2, HRH1, and HTR2A genes may affect
its biopharmaceutical properties and also the manifesta-
tion of potential adverse drug reactions [25] (Table 2).
4.15. Periciazine
Periciazine is a piperidine phenothiazine which blocks
postsynaptic mesolimbic dopaminergic D1 and D2 re-
ceptors, and α-adrenergic receptors, also acting as an
inverse agonist of 5-HT6 and 5-HT7 receptors, and an
antagonist of 5-HT2A and 5-HT2c receptors. This typical
antipsychotic is a substrate of CYP2D6 and CYP3A4.
Caution and personalized dose adjustment should be
made in patients with the following genotypes: CYP2D6
(CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6,
CYP2D6*7, CYP2D6*8, CYP2D6*10, CYP2D6*17,
CYP2D6*1xN), and CYP3A4 (CYP3A4*3). ADRA1A,
DRD1, DRD2, DRD3, HTR2A, HTR2C, HTR6, HTR7
variants may influence its pharmacokinetic and pharma-
codynamic properties [25] (Table 2).

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 118
4.16. Perphenazine
Perphenazine is a piperazine phenothiazine which blocks
postsynaptic mesolimbic dopaminergic D1 and D2 recep-
tors. This typical antipsychotic is a major substrate of
CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19,
CYP2D6, and CYP3A4/5, and a weak inhibitor of
CYP1A2 and CYP2D6. Caution and personalized dose
adjustment should be made in patients with the following
genotypes: ADRA1A (Arg347Cys), CYP2D6 (CYP2D6*3,
CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7,
CYP2D6*8, CYP2D6*10, CYP2D6*17), and DRD2
(−141C Ins/Del (rs1799732), TaqlA (rs1800497), TaqIB
(rs1079597), rs1125394). ABCB1, CYP1A2, CYP2C9,
CYP2C19, CYP3A4, DRD1, and RGS4 variants may
affect its biopharmaceutical properties [25] (Table 2).
4.17. Pimozide
Pimozide is a diphenylbutylpiperidine with antagonistic
activity on dopaminergic receptors and 5-HT1A, 5-HT2A
and 5-HT7 receptors. This typical antipsychotic is a ma-
jor substrate of CYP3A4, a minor substrate of CYP1A2,
a weak inhibitor of CYP2C19 and CYP2E1, a moderate
inhibitor of CYP3A4, and a strong inhibitor of CYP2D6.
Caution and personalized dose adjustment should be
made in patients with the following genotypes:
ADRA1A (Arg347Cys), CYP1A2 (C734A, G-2964A),
CYP2D6 (CYP2D6*3, CYP2D6*4, CYP2D6*5,
CYP2D6*6, CYP2D6*7, CYP2D6*8, CYP2D6*10,
CYP2D6*17, CYP2D6*1xN), CYP3A4 (CYP3A4*3),
KCNE2 (Gln9Glu, Met54Thr,Thr8Ala), KCNH2
(Arg784Trp), KCNQ1 (Arg583Cys), and SCN5A
(Gly615Glu, Leu618Phe, Phe1250Leu, Leu1825Pro).
Other genes potentially involved in its metabolism and
pharmacological properties are ABCB1, CHRM2,
CYP2C19, CYP2E1, DRD2, KCNE1, and KCNJ11 [25]
(Table 2).
4.18. Pipotiazine
Pipotiazine is a piperidine phenothiazine which blocks
postsynaptic mesolimbic dopaminergic D1 and D2 recep-
tors. This typical antipsychotic is a substrate of CYP2D6
and CYP3A4. Different polymorphic variants in the
CYP2D6, CYP3A4, and DRD genes may affect its me-
tabolism and pharmacological properties [25] (Table 2).
4.19. Prochlorperazine
Prochlorperazine is a piperazine phenothiazine which
strongly blocks postsynaptic mesolimbic dopaminergic
D1 and D2 receptors, α-adrenergic receptors and cho-
linergic receptors. The metabolism and pharmacologi-
cal properties of this typical antipsychotic may be af-
fected by polymorphic variants in the ABCB1, ADRA1A,
CYPs, DRD1, and DRD2 genes, as well as other genes
associated with histaminergic and cholinergic neuro-
transmission [25] (Table 2).
4.20. Quetiapine
Quetiapine is a dibenzothiazepine which acts as a sero-
tonergic (5-HT1A, 5-HT2A, 5-HT2), dopaminergic (D1 and
D2), histaminergic H1, and adrenergic (α1- and α2-) re-
ceptor antagonist, and a full agonist of 5-HT1A, 5-HT1D,
5-HT1F, and 5-HT2A receptors. This atypical antipsy-
chotic is a minor substrate of CYP2D6 and a major sub-
strate of CYP3A4/5. Caution and personalized dose ad-
justment should be made in patients with the following
genotypes: ADRA1A (Arg347Cys), CYP3A4
(CYP3A4*3), HTR2A (His452Tyr, His368Tyr, Ile197Val,
Ile113Val, Ala447Val, Ala363Val, Thr25Asn), KCNE2
(Gln9Glu, Met54Thr, Thr8Ala), KCNH2 (Arg784Trp),
KCNQ1 (Arg583Cys), and SCN5A (Gly615Glu,
Leu618Phe, Phe1250Leu, Leu1825Pro). These geno-
types and other polymorphisms in the ABCB1, CYP2D6,
DRD1, DRD2, DRD4, HRH1, HTR1A, HTR2B,
KCNE1, and RGS4 genes are responsible for the me-
tabolism and biopharmaceutical properties of quetiapine
[25] (Table 2).
4.21. Risperidone
Risperidone is a benzisoxazole with serotonergic, dopa-
minergic, α1-, α2-adrenergic and histaminergic receptor
antagonist activity, low-moderate affinity for 5-HT1C,
5-HT1D, and 5-HT1A receptors, low affinity for D1 recep-
tors, and inverse agonist activity on 5-HT2c, 5-HT6, and
5-HT7 receptors. This atypical antipsychotic is a major
substrate of ABCB1 and CYP2D6, a minor substrate of
CYP3A4/5, and weakly inhibits ABCB1, CYP2D6, and
CYP3A4. Caution and personalized dose adjustment
should be made in patients with the following genotypes:
ABCB1 (C1236T, G2677T, C3435T), COMT (rs4633,
rs4680, rs737865, rs6269, rs4818, rs165599), CYP2D6
(CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6,
CYP2D6*7, CYP2D6*8, CYP2D6*10, CYP2D6*17),
DRD2 (TaqIA (rs1800497), −141C Ins/Del (rs1799732),
A-241G), DRD3 (Gly9Ser (rs6280), rs167771), GRM3
(rs724226), HTR2A (His452Tyr, His368Tyr, Ile197Val,
Ala447Val, Ala363Val, Thr25Asn, 102-T/C (rs6313)),
HTR3A (rs1176713), and HTR6 (T267C). These geno-
types and other variants in the ADRA1A, ADRA1B,
APOA5, CYP3A4/5, DRD1, DRD4, FOS, HTR2C,
KCNH2, RGS4, and SLC6A4 genes are responsible for
the metabolism, pharmacological effects, and adverse
drug events associated with risperidone administration to
psychotic patients [25] (Table 2).
4.22. Sulpiride
Sulpiride is a benzamide with postsynaptic D2 antagonist

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 119
activity. This atypical antipsychotic is a substrate of
CYP2D6, and polymorphisms in the CYP2D6 and DRD2
genes influence its metabolism and pharmacological
properties [25] (Table 2).
4.23. Thioridazine
Thioridazine is a phenothiazine which blocks postsynap-
tic mesolimbic dopaminergic receptors and α-adrenergic
receptors, also acting as an inverse agonist of 5-HT6 and
5-HT7 receptors, and as an antagonist of 5-HT2c receptors.
This typical antipsychotic is a major substrate of
CYP1A2, CYP2D6, CYP2J2, and CYP3A4, a minor
substrate of CYP2C19, a weak inhibitor of CYP1A2,
CYP2C9, CYP2E1, and DRD1, a moderate inhibitor of
CYP2D6, and a strong blocker of ADRA1s, ADRA2s,
and ADRBs. Caution and personalized dose adjustment
should be made in patients with the following genotypes:
ADRA1A (Arg347Cys), CYP2D6 (CYP2D6*3,
CYP2D6*4, CYP2D6*5, CYP2D6*6, CYP2D6*7,
CYP2D6*8, CYP2D6*10, CYP2D6*17), and KCNE2
(Gln9Glu, Met54Thr, Thr8Ala). Other genes that may be
involved in thioridazine metabolism and pharmacologi-
cal effects include ABCB1, CHRM2, CYP1A2, CYP2A6,
CYP2C9, CYP2C19, CYP2E1, CYP2J2, CYP3A4,
DRD2, FABP1, HRH1, KCNE1, KCNH2, KCNQ1, and
KCNJ11 [25] (Table 2).
4.24. Thiothixene
Thiothixene is a thioxanthene which inhibits dopamine
receptors, blocks α-adrenergic receptors, and is an an-
tagonist of 5-HT2a receptors. This typical antipsychotic is
a major substrate of CYP1A2 and a weak inhibitor of
CYP2D6. Caution and personalized dose adjustment
should be made in patients with the following genotypes:
ADRA1A (Arg347Cys), CYP1A2 (C734A, G-2964A),
KCNE2 (Gln9Glu, Met54Thr, Thr8Ala), KCNQ1
(Arg583Cys), KCNH6 (Arg784Trp), and SCN5A
(Gly615Glu, Leu618Phe, Phe1250Leu, Leu1825Pro).
Other genes potentially involved in thiothixene metabo-
lism and pharmacological effects are CYP2D6, DRD2,
and KCNE1 [25] (Table 2).
4.25. Trifluoperazine
Trifluoperazine is a phenothiazine which blocks post-
synaptic mesolimbic dopaminergic receptors and α-ad-
renergic receptors. This typical antipsychotic is a major
substrate of CYP1A2 and UGT1A4. Caution and per-
sonalized dose adjustment should be made in patients
with the following genotypes: ADRA1A (Arg347Cys),
and CYP1A2 (C734A, G-2964A). Some other genes
(ABCB1, DRD2, IL12B, UGT1A4) may affect trifluop-
erazine pharmacokinetics and pharmacodynamics [25]
(Table 2).
4.26. Ziprasidone
Ziprasidone is a benzylisothiazolylpiperazine with high
affinity for D2, D3, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT1D and
α1-adrenergic receptors; moderate affinity for histamine
H1 receptors; antagonist of D2, 5-HT1A, 5-HT2A, and
5-HT1D receptors; full agonist of 5-HT1B and 5-HT1D
receptors; partial agonist of 5-HT1A receptors; and in-
verse agonist of 5-HT2c and 5-HT7 receptors. This atypi-
cal antipsychotic is a major substrate of CYP3A4, a mi-
nor substrate of CYP1A2, a substrate of AOXs and
HTR1A, and an inhibitor of CYP2D6, CYP3A4, HTR2A,
and DRD2. Caution and personalized dose adjustment
should be made in in patients with the following geno-
types: CYP3A4 (CYP3A4*1, CYP3A4*1B, CYP3A4*2,
CYP3A4*3, CYP3A4*4, CYP3A4*5, CYP3A4*6,
CYP3A4*8, CYP3A4*11, CYP3A4*12, CYP3A4*13,
CYP3A4*15, CYP3A4*17, CYP3A4*18, CYP3A4*19),
HTR2A (His452Tyr, His368Tyr, Ile197Val, Ile113Val,
Ala447Val, Ala363Val, Thr25Asn), KCNH2 (Tyr652Ala,
Phe656Ala), and RGS4 (rs951439, rs2661319, rs2842030).
Other genes involved in ziprasidone pharmacokinetics
and pharmacodynamics include AOX1, CYP1A2,
CYP2D6, DRD2, DRD4, HTR1A, HTR2A, HRH1, and
KCNH2 [25] (Table 2).
4.27. Zuclopenthixol
Zuclopenthixol is a thioxanthene which blocks post-
synaptic mesolimbic dopaminergic receptors. This typi-
cal antipsychotic is a major substrate of CYP2D6; con-
sequently, caution and personalized dose adjustment
should be made in patients with the following CYP2D6
variants: CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*6,
CYP2D6*7, CYP2D6*8, CYP2D6*10, CYP2D6*17,
CYP2D6*1xN. Other genes to take into account in the
pharmacokinetics and pharmacodynamics of zuclopen-
thixol are ADRA1A, DRD1, DRD2, KCNE2, and
SCN5A [25] (Table 2).
5. FUTURE DIRECTIONS
Historically, the vast majority of pharmacogenetic stud-
ies of CNS disorders have been addressed to evaluate the
impact of cytochrome P450 enzymes on drug metabo-
lism, and conventional targets for psychotropic drugs
were dopamine, serotonin, noradrenaline, GABA, ion
channels, acetylcholine and their respective biosynthetic
and catalyzing enzymes, receptors and transporters;
however, in the past few years many different genes have
been associated with both pathogenesis and pharmaco-
genomics of neuropsychiatric disorders [1,2,5,6,17].
Some of these genes and their products constitute poten-
tial targets for future treatments. New developments in
genomics, including whole genome genotyping ap-
proaches and comprehensive information on genomic

R. Cacabelos et al. / Open Journal of Psychiatry 2 (2013) 46-139 120
variation across populations, coupled with large-scale
clinical trials in which DNA collection is routine, now
provide the impetus for a next generation of pharmaco-
genetic studies and identification of novel candidate
drugs.
Priority areas for pharmacogenetic research are pre-
dicting serious adverse reactions (ADRs) and establish-
ing variation in efficacy [348]. Both requirements are
necessary in CNS disorders to cope with efficacy and
safety issues associated with both current psychotropic
drugs and new drugs. Since drug response is a complex
trait, genome-wide approaches may provide new insights
into drug metabolism and drug response. Of paramount
importance is the identification of polymorphisms af-
fecting gene regulation and mRNA processing in genes
encoding cytochrome P450s and other drug-metabolizing
enzymes, drug transporters, and drug targets and recep-
tors, with broad implication in pharmacogenetics since
functional polymorphisms which alter gene expression
and mRNA processing appear to play a critical role in
shaping human phenotypic variability [349]. It is also
most relevant, from a practical point of view, to under-
stand the pharmacogenomics of drug transporters, espe-
cially ABCB1 (P-glycoprotein/MDR1) variants, due to
the pleiotropic activity of this gene on a large number of
drugs [350]. It is necessary to have a better documenta-
tion related to the pharmacogenetic roles of the enor-
mous number (>170) of human solute carrier transporters
which transport a variety of substrates, including amino
acids, lipids, inorganic ions, peptides, saccharides, metals,
drugs, toxic xenobiotics, chemical compounds, and pro-
teins [351]. RNAi pharmacogenomics will also bring
new insights into the nature and therapeutic value of
gene silencing in CNS disorders [352-356].
The optimization of CNS therapeutics, in general, and
the pharmacological treatment of SCZ and psychotic
disorders, in particular, requires the establishment of new
postulates regarding 1) the costs of medicines; 2) the
assessment of protocols for multifactorial treatment in
chronic disorders; 3) the implementation of novel thera-
peutics addressing causative factors; and 4) the seting-up
of pharmacogenomic strategies for drug development
and drugs on the market [2,6,14].
By knowing the pharmacogenomic profiles of patients
who require treatments with psychotropic drugs of cur-
rent use, it might be possible to obtain some of the fol-
lowing benefits: 1) to identify candidate patients with the
ideal genomic profile to receive a particular drug; 2) to
adapt the dose in over 60% - 90% of the cases according
to the condition of EM, IM, PM or UM (diminishing the
occurrence of direct side-effects in 30% - 50% of the
cases); 3) to reduce drug interactions by 30% - 50%
(avoiding the administration of inhibitors or inducers
able to modify the normal enzymatic activity on a par-
ticular substrate); 4) to enhance efficacy and pharma-
codynamic specificity; and 5) to eliminate unnecessary
costs (>30% of pharmaceutical costs) derived from the
consequences of an inappropriate drug selection and the
overmedication administered to mitigate ADRs.
6. ACKNOWLEDGEMENTS
We thank Carmen Fraile and Adam McKay for technical support.
Most studies on pharmacogenomics of CNS disorders in our institu-
tion are funded by the International Agency for Brain Research and
Aging (IABRA).
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