Open Journal of Genetics, 2013, 3, 38-45 OJGen Published Online August 2013 (
Hormonally modulated migraine is associated with
single-nucleotide polymorphisms within genes involved
in dopamine metabolism
Amy K. Sullivan1*, Elizabeth J. Atkinson2, F. Michael Cutrer1
1Division of Headache, Mayo Clinic, Rochester, USA
2Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, USA
Email: *
Received 2 July 2013; revised 10 July 2013; accepted 20 July 2013
Copyright © 2013 Amy K. Sullivan et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Migraine is a complex trait in which multiple genetic
loci, as well as environmental factors, likely contrib-
ute to its clinical manifestation. Many genetic asso cia-
tions reported in previous studies either have not
been replicated to date or showed only marginal sta-
tistical significance, possibly due to the genetic het-
erogeneity of the common forms of migraine. One
major phenotypic and possibly genetically identifiable
migraine subgroup consists of women whose attacks
are influenced by fluctuation in gonadal hormones.
We hypothesized that for these women, the associa-
tion between migraine attacks and the menstrual cy-
cle might be attributable to an increased prevalence
of genetic polymorphisms in the hypothalamic-pitui-
tary-gonadal axis. We selected 21 such polymer-
phisms previously reported to be associated with the
common forms of migraine and genotyped 1740 indi-
viduals (1132 migraineurs) to determine whether any
of these selected polymorphisms occurred more fre-
quently in females with hormonally modulated mi-
graine. We were able to confirm the association of
migraine with 3 genetic polymorphisms seen in pre-
vious studies (rs4680 [COMT], rs2283265 [DRD2],
and rs7131056 [DRD2]). Interestingly, we found 2
additional genetic polymorphisms (rs2070762 [TH]
and rs6356 [TH]) to be associated with migraine when
defining the phenotype as hormonally modulated mi-
Keywords: Genetic Polymorphism; Headache;
Hypothalamic Hormone; Menstrual Cycle; Menstruation
Migraine is a debilitating, heterogeneous neurologic dis-
order affecting over 35 million Americans [1,2] and cost-
ing the American economy over 19 billion dollars annu-
ally [3,4]. Three-quarters of people with migraine are
women [1,2]. Migraine is a complex trait in which mul-
tiple genetic loci, as well as environmental factors, likely
contribute to its clinical manifestation [5]. Many genetic
associations reported in previous studies either have not
been replicated to date or showed only marginal statisti-
cal significance, possibly because of the genetic hetero-
geneity of common forms of migraine [6]. Given the cli-
nical heterogeneity of migraine, it is important to clearly
define the phenotype to better isolate the genetic com-
ponent. One major phenotypic and possibly genetically
identifiable migraine subgroup consists of women whose
attacks are influenced by fluctuation in gonadal hor-
mones. Given that almost 60% of women with migraine
report that their attacks are more severe or frequent
around the time of menstrual flow [7-10], variation in the
genes coding for enzymes and receptors involved in the
secretion and regulation of gonadal hormones may be a
major source of migraine susceptibility.
Considerable circumstantial evidence implicates per-
turbation of the hypothalamic-pituitary-gonadal axis in
migraine. Previous studies have shown that in some
women, migraine attacks frequently are associated with
dramatic decreases in estrogen during the menstrual cy-
cle [11-13]. Furthermore, a rodent-based study showed
enhanced sensitization of the trigeminal nucleus caudalis
immediately after a decrease in ovarian hormone levels
[14], consistent with differing trigeminal excitability
among menstrual migraineurs [15].
Single-nucleotide polymorphisms (SNPs) rs1801132,
rs2228480, and rs2234693 located within the estrogen
*Corresponding author.
A. K. Sullivan et al. / Open Journal of Genetics 3 (2013) 38-45 39
receptor 1 gene (ESR1 [MIM 133430]), rs4986938 lo-
cated within the estrogen receptor 2 gene (ESR2 [MIM
601663]), and rs1042838 located within the progesterone
receptor gene (PGR [MIM 607311]) have been associ-
ated with migraine previously [16-21]. The physiology of
the hypothalamic-pituitary-gonadal axis is complex, and
although the nature of its exact interaction with migraine
is not yet understood, the crosstalk between dopamine,
norepinephrine, and endorphins (neurotransmitters in-
volved in the hypothalamic-pituitary-gonadal axis and in
pain) is well known [22-26]. In fact, after the estrogen is
converted to catechol estrogen, the metabolism of go-
nadotropin-releasing hormone (GnRH) and catechola-
mines are intimately influenced by one another. Catechol
estrogens can inhibit tyrosine hydroxylase (TH [MIM
191290]) and compete for catechol-O-methyltransferase
(COMT [MIM 116790]) (Figure 1) [26], indicating that
estrogen levels may greatly influence catecholamine lev-
In previous studies, several genes involved in dopa-
mine metabolism were implicated in migraine suscepti-
bility. Genetic polymorphisms in COMT (rs4680), TH (rs
6356 and rs2070762), solute carrier family 6 member 3
(SLC6A3 [MIM 126455]) dopamine transporter (rs40184),
dopa decarboxylase (DDC [MIM 107930]) (rs2329340),
dopamine beta-hydroxylase (DBH [MIM 609312]) (rs
1611115, rs2097629, and a 19-base pair insertion/dele-
tion polymorphism [27] in the promoter region), and do-
pamine receptors D2 (DRD2 [MIM 126450]) (rs6275,
rs1554929, rs2234689, rs2242592, rs2283265, rs7131056,
and rs12363125) and D4 (DRD4 [MIM 126452]) (48-
base pair tandem repeat in exon III [28]) have been
found to be associated with migraine [29-38]. However,
the vast majority of SNP associations listed above have
not been replicated [31].
In this study, we hypothesized that the association be-
tween migraine and the menstrual cycle might be attrib-
utable to increased prevalence of polymorphisms within
genes involved in the hypothalamic-pituitary-gonadal
axis (observed previously in male and female migrai-
neurs). We selected 21 such polymorphisms previously
reported to be associated with the common forms of mi-
graine and genotyped 1740 individuals (1132 migrain-
eurs) to determine whether any of these selected poly-
morphisms occurred more frequently in females with
hormonally modulated migraine (HMM).
2.1. Study Population and Selection Criteria
All individuals who participated in this study gave in-
formed consent. The informed consent forms and proto-
cols of this study were approved by the Mayo Clinic In-
stitutional Review Board.
Migraine cases were ascertained using questionnaires
based on the International Headache Society’s diagnostic
criteria (The International Classification of Headache
Disorders, second edition [ICHD-II]) [39]. All elements
Figure 1. Catecholestrogens and their role in catecholamine metabolism. After estradiol is con-
verted to catecholestrogen by estradiol 2-hydroxylase, the metabolism of gonadotropin-releas-
ing hormone and catecholamines are intimately influenced by each other, as catecholestrogens
can inhibit tyrosine hydroxylase and compete for catechol-O-methyltransferase (Adapted from
Speroff and Fritz [26]. Used with permission).
Copyright © 2013 SciRes. OPEN ACCESS
A. K. Sullivan et al. / Open Journal of Genetics 3 (2013) 38-45
of the clinical phenotype were stored in the Mayo Head-
ache Registry, a computerized data entry system that
allows complex analysis of any data element, either
separately or in tandem. Patients included in the Mayo
Headache Registry were seen specifically for headache
concerns in the outpatient setting in the Headache Divi-
sion of the Neurology Department at Mayo Clinic (Ro-
chester, Minnesota) or were volunteers (i.e., Mayo em-
ployees and trainees or local residents). Study subjects
were recruited from 2006 through 2011. All question-
naires were completed in the presence of the investi-
gators or study staff to address any questions raised by
the subject. Blood samples were collected from indi-
viduals with migraines diagnosed on the basis of the
ICHD-II [39] and were included in the Mayo Migraine
Genomic Library, a DNA repository of migraine cases
and age- and sex-matched controls.
Control subjects were recruited from the same volun-
teer pools as the case subjects. Individuals who qualified
as control subjects had to indicate that they never had a
migraine or probable migraine headache, as determined
by their responses to a questionnaire administered by the
study staff. Family history also was considered; only
those subjects whose parents and siblings also had no
history of migraine were included in the Mayo Migraine
Genomic Library as controls.
Among the phenotypic data elements obtained from all
female subjects was whether the migraine attacks oc-
curred with greater frequency and intensity around the
time of menstrual flow. The possible responses to this
question were: 1) yes, the migraine attacks occur with
greater frequency and intensity around the time of men-
struation; 2) no, the migraine attacks do not occur with
greater frequency and intensity around the time of men-
struation; 3) I do not know; or 4) this question does not
apply to me. Although human recall is imperfect, these 4
choices provide 2 answers for women who are unsure of
the relationship of their attacks with menstruation; this
increases the likelihood that the subjects are accurate in
their response and minimizes recall bias.
The purpose of this study was to investigate the rela-
tionship between genotype and the phenotypic trait of
menstrual modulation of migraine attacks, rather than to
examine the characteristics of individual attacks. Thus,
we opted not to use the ICHD-II appendix provisional
diagnoses of pure menstrual migraine or menstrual-re-
lated migraine for this study because they required head-
aches to occur within 2 days (before or after) the first day
of menstrual flow. Although such narrow definitions are
important in therapeutic trials, they are not optimal in a
large genetic-association study.
2.2. Genetic Polymorphism Selection and
We conducted a literature search and identified 21 poly-
morphisms in genes involved in the hypothalamic-pi-
tuitary-gonadal axis, which drives menstrual flow [16-
21,27,29-36]; these polymorphisms previously were re-
ported to be associated with the common forms of mi-
graine (Table 1). We aimed to determine whether any of
these associations held true in our study population.
Our initial analysis comparing cases and controls was
performed using the entire dataset (males and females) to
determine whether we could replicate findings found in
previous studies. Our second analysis specifically con-
sidered only female cases and controls. Our third analy-
sis compared women with nonhormonally modulated mi-
graine (NHMM) vs female controls. Lastly, we com-
pared women with HMM vs female controls.
2.3. Genotyping
DNA isolation was performed at the Biospecimens Ac-
cessing and Processing Core Facility at Mayo Clinic.
Briefly, DNA from whole blood was purified using the
Flex Star genomic DNA isolation instrument (Autogen,
Inc) and the Flexigene DNA kit (Qiagen, Inc). Once pu-
rified, the DNA was quantified with a Nanodrop ND-
8000 spectrophotometer (Thermo Fisher Scientific, Inc).
The DNA samples were activated through a chemical
reaction with biotin. Biotinylated DNA was purified to
remove excess biotin. Assay oligonucleotides were hy-
bridized to the DNA, and the mixture was bound to
streptavidin-conjugated paramagnetic particles. Hybrid-
ized oligonucleotides underwent allele specific primer
extension and ligation, and the products formed a syn-
thetic template that was amplified via a polymerase chain
reaction (PCR). The strand containing the fluorescent
signal in the PCR products was isolated and hybridized
to VeraCode universal capture bead sets (Illumina, Inc.)
via an address sequence. The BeadXpress reader system
and BeadStudio data analysis software (Illumina, Inc.)
were used to automatically identify alleles. The genotype
of the SNP was determined by the ratio of the relative
fluorescent levels of the 2 bead types.
The variable number of tandem repeats (VNTR)
polymorphisms in both the DBH and DRD4 genes was
analyzed using a 3730XL DNA sequencer (Applied Bio-
systems, Inc.). Briefly, PCR amplification was per-
formed using TaqGold, with specific primers to amplify
the regions of interest (Applied Biosystems, Inc). For
DBH VNTR, the forward primer sequence was
verse primer sequence was
VNTR, PCR was performed with the primer set
5’-GCGACTACGTGGTCTACTCG-3’. Genotypes were
identified using GeneMapper software (Applied Biosys-
tems, Inc). Allele identification was based on known ge-
Copyright © 2013 SciRes. OPEN ACCESS
A. K. Sullivan et al. / Open Journal of Genetics 3 (2013) 38-45 41
Table 1. Genetic polymorphisms in the hypothalamic-pituitary-gonadal axis previously reported to be associated with migraine.
Reference SNP Number Gene Name Encoded Protein Chromosome Study
rs40184 SLC6A3 Solute carrier family 6 (neuro-transmitter
transporter, dopamine), member 3 5 32
ESR1 Estrogen receptor 1 6
rs2329340 DDC Dopa decarboxylase
(aromatic L-amino acid decarboxylase) 7 33
Promoter region, 19 base pair
DBH Dopamine beta-hydroxylase
(dopamine beta-mono-oxygenase) 9
DRD2 Dopamine receptor D2 11
rs2070762 TH Tyrosine hydroxylase 11 31
rs1042838 PGR Progesterone receptor 11 16
Exon III, 48-base pair tandem repeatDRD4 Dopamine receptor 11 37
rs4986938 ESR2 Estrogen receptor 2 (ER beta) 14 17
rs4680 COMT Catechol-O-methyltransferase 22 29.30
notype and size standards described in previous studies
2.4. Statistical Analyses
Before conducting statistical analyses, general quality
control checks were performed on the genotype data.
Polymorphisms with call rates less than 95%, SNPs with
minor allele frequencies less than 5%, and polymerphi-
sms that deviated from Hardy-Weinberg equilibrium (P
< 105) were closely examined because these are indi-
cators of potential clustering problems. Samples with call
rates less than 95% were excluded from the analysis. The
association of each polymorphism with migraine was
evaluated by logistic regression using age and sex as
covariates to account for confounding variables. Di-alle-
lic markers were tested using the additive genetic model,
in which genotypes are coded as 0, 1, or 2, according to
the number of rare variants. The VNTR was tested using
indicators for carrier status of the common variants and
by using a single count for the number of repeats. The t
test and χ2 test were used to test for group differences of
continuous and categorical variables, respectively.
3.1. Study Population
Our study population included 1740 subjects (1132 cases,
608 controls). Figure 2 shows how cases and controls
were further divided into subgroups on the basis of sex
and presence or absence of HMM. Age and race (per-
centage white) were similar between cases and controls
(Table 2). Results remained statistically significant when
conducting statistical analyses among whites only.
3.2. Identification of SNPs Associated with
Table 3 summarizes the SNPs with confirmed associa-
tion with migraine. With logistic regression analyses ap-
plied to the full study cohort, we identified SNPs rs4680
(COMT), rs2283265 (DRD2), and rs7131056 (DRD2) as
being associated with migraine. Considering the female-
only subgroup, rs4680 (COMT) was still significantly
associated with migraine. No SNPs were associated with
migraine when comparing females with NHMM (n = 364)
vs controls (n = 350); specifically, the COMT SNP rs
4680 was not significantly associated with migraine in
this subgroup (odds ratio, 1.18; 95% CI, 0.95 - 1.42; P =
When comparing women with HMM vs female con-
trols, we again identified SNPs from COMT and DRD2.
However, we also identified 2 additional SNPs, rs2070762
and rs6356 (both within TH ), as having significant asso-
ciation with migraine. Of note, SNP rs7131056 (DRD2)
was not significantly associated with migraine in this
subgroup (OR, 1.10; 95% CI, 0.90 - 1.35; P = 0.35).
Copyright © 2013 SciRes. OPEN ACCESS
A. K. Sullivan et al. / Open Journal of Genetics 3 (2013) 38-45
Table 2. Study population characteristics.
Controls Cases
(N = 1740) All
(n = 608) Females
(n = 350) All
(n = 11 32 ) Females
(n = 892) HMM
(n = 464) NHMM
(n = 364)
Age, mean (SD), y 33.89 (8.22)34.49 (8.09) 34.71 (7.95)33.57 (8.27) 33.30 (7.90) 34.72 (7.81) 32.07 (7.87)
Range 18 - 50 19 - 50 21 - 50 18 - 50 18 - 50 18 - 50 18 - 49
White race, No. (%) 1651 (94.89)555 (91.29) 333 (95.14) 1096 (96.82) 867 (97.20) 452 (97.41) 351 (96.43)
Abbreviations: HMM, hormonally modulated migraine; NHMM, nonhormonally modulated migraine.
Table 3. SNPs associated with migraine.
Group Cases, No. Controls, No. SNP (Gene) Odds Ratio (95% CI) P Value
All cases (N = 1740) 1132 608
rs4680 (COMT)
rs2283265 (DRD2)
rs7131056 (DRD2)
1.25 (1.09 - 1.45)
1.22 (1.01 - 1.47)
1.18 (1.03 - 1.35)
Females only (n = 1242) 892 350 rs4680 (COMT) 1.2 (1.02 - 1.43) 0.03
HMM vs female controls (n = 814) 464 350
rs4680 (COMT)
rs2283265 (DRD2)
rs2070762 (TH)
rs6356 (TH)
1.23 (1.02 - 1.52)
1.37 (1.05 - 1.82)
1.23 (1.01 - 1.49)
1.24 (1.01 - 1.53)
Abbreviations: HMM, hormonally modulated migraine; SNP, single-nucleotide polymorphism.
Figure 2. Study population. Blood samples were collected from
individuals with a migraine diagnosis and from age- and sex-
matched controls. Details of classification criteria are described
in the Methods. HMM denotes hormonally modulated migraine;
NHMM, nonhormonally modulated migraine.
In our large cohort of 1740 individuals, we surveyed 21
genetic polymorphisms previously shown to be associ-
ated with migraine, with gene products that were in-
volved in the hypothalamic-pituitary-gonadal axis. We
were able to confirm the association of migraine with 3
SNPs: rs4680 (COMT), rs2283265 (DRD2), and rs7131056
(DRD2) [29,30,32,40]. To our knowledge, this is the first
study to confirm these associations to date.
We then tested our hypothesis that the genetic poly-
morphisms previously reported to be associated with
migraine were more common in females whose migraine
attacks were influenced by their menstrual cycle. When
we defined the clinical phenotype as women with HMM,
4 SNPs (rs4680, rs2283265, rs2070762, and rs6356) lo-
cated within genes COMT, DRD2, and TH showed sig-
nificant associations, even though the number of cases in
the subgroup was smaller than the initial study group.
However, the rs7131056 (DRD2) association was no
longer significant in this subanalysis, possibly because of
the smaller number of cases. No SNPs were found to be
associated with migraine when cases were limited to
women with NHMM.
By narrowing the study group to a more homogenous
clinical migraine phenotype, we were able to better de-
tect the association of several genetic polymorphisms
with migraine. Our findings suggest that women with
HMM may have an underlying pathophysiologic mecha-
nism that is distinct from that of women whose migraines
are not modulated by the hypothalamic-pituitary-gonadal
axis. Conversely, these findings also suggest that women
with NHMM may be a more genetically heterogeneous
group, or at least their association with migraine is not
based on variation in the hypothalamic-pituitary-gonadal
axis-related genes that we studied.
Notably, all genetic polymorphisms found to be asso-
ciated with migraine in the current study were involved
in dopamine metabolism. Why might this be the case?
One possibility is that dopamine metabolism is an impor-
tant interface between the hypothalamic-pituitary-gona-
dal axis and pain modulation. Dopamine in the central
nervous system is known to have a role in pain modula-
tion [40,41] and in fact has been implicated in migraine
pathophysiology [42]. In rodent models, dopamine can
block nociceptive signal transmission at the level of the
trigeminocervical complex by binding D2-like receptors
Copyright © 2013 SciRes. OPEN ACCESS
A. K. Sullivan et al. / Open Journal of Genetics 3 (2013) 38-45 43
[43]. Also, trigeminal nociceptive transmission is influ-
enced by the dopaminergic A11 nucleus [44]. Other key
players in dopamine metabolism have also been shown
to affect pain modulation. Inhibition of COMT increased
pain sensitization in mice [45], and stress-induced anal-
gesia was altered in COMT-deficient mice [46].
Dopamine is important not only in pain modulation
but also in the catechol estrogen metabolism pathway.
Specifically, in the brain, estrone and estradiol can be
converted into catechol estrogens by 2-hydroxylase. At
the level of the anterior pituitary, catechol estrogens may
compete with dopamine for dopamine-binding sites and
may even inhibit the synthesis and metabolism of dopa-
mine [47]. In rats, catechol estrogens decrease the turn-
over rate of dopamine in the corpus striatum [48]. Also,
animal studies have shown that dopamine influences
GnRH production at the level of the hypothalamus [49-
52]. In fact, in vitro data suggest that dopamine can sti-
mulate GnRH secretion from the human hypothalamus
[53]. Some evidence suggests that D1 receptor stimula-
tion increases pituitary responsiveness to GnRH in wo-
men [54]. Clearly, dopamine and estrogen pathways are
intimately associated on several levels, which may ex-
plain the association of dopamine-related genetic poly-
morphisms with migraine in women whose headaches
are influenced by their menstrual cycles.
As with other complex traits, clinical heterogeneity
confounds identification of the genetic underpinnings of
migraine. Thus, careful detailed ascertainment of clinical
phenotype in the sample population is likely to be of
great importance. The ability to segregate case subjects
into more clinically homogenous groups on the basis of
biologic characteristics may prove invaluable for unrav-
eling the genetic components of complex traits such as
A possible weakness of our study was the relative lack
of ethnic diversity in our cohort. Migraine affects indi-
viduals across all racial groups. However, given our geo-
graphic location (Rochester, Minnesota), greater than
90% of subjects were white in both the case and control
groups, and the remaining subjects comprised more than
20 different ethnicities. Nevertheless, when conducting
statistical analyses among whites only, our results re-
mained statistically significant.
In this study, by defining the clinical phenotype as
women with HMM, we were better able to identify addi-
tional associated genetic polymorphisms. Intriguingly, all
the genetic polymorphisms that we identified or con-
firmed as significantly associated with migraine were in
genes involved in dopamine metabolism. Dopamine is
important not only in pain modulation but also in cate-
chol estrogen metabolism. The importance of dopamine
in migraine may be due to its function at the interface of
the hypothalamic-pituitary-gonadal axis and pain modu-
lation. More studies investigating this association are
This work was supported through a grant from the Mayo Clinic
Women’s Health Research program. We would also like to express our
appreciation to the Mayo Clinical Research Fund, GlaxoSmithKline,
the Migraine Research Foundation, and Mary Ella Jerome for their
unrestricted support of the Mayo Migraine Genomic Library.
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