Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility
BMC Medical Genetics
Investigation of Gamma-aminobutyric acid (GABA) A receptors genes and migraine susceptibility
Francesca Fernandez 2
Teresa Esposito 1
Rod A Lea 0 2
Natalie J Colson 2
Alfredo Ciccodicola 1
Fernando Gianfrancesco 1
Lyn R Griffiths 2
0 Institute of Environmental Science and Research , Wellington , New Zealand
1 Institute of Genetics and Biophysics , Adriano Buzzati-Traverso, CNR, Naples , Italy
2 Genomics Research Centre, Griffith Institute for Health and Medical Research, Griffith University , Gold Coast, Queensland , Australia
Background: Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24-28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ), which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24-28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type (GABRE) and type (GABRQ) genes and their involvement in migraine. Methods: We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls) examining a set of 3 single nucleotide polymorphisms (SNPs) in the coding region (exons 3, 5 and 9) of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results: Our study did not show any association between the examined SNPs in our test population (P > 0.05). Conclusion: Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.
Migraine is a common neurological disorder with variable
expression, affecting more than 12% of the general
population . The exact cause is unknown and there are no
recognizable diagnostic pathological changes. Migraine is
a neurological disorder, characterised by recurrent
headache that is associated with nausea and/or vomiting,
photophobia and phonophobia. The International Headache
Society (IHS) has formally classified migraine into two
main subtypes: migraine with aura (MA) and migraine
without aura (MO) . These two subtypes have
substantial symptomatic overlap, but MA sufferers experience
distinguishing neurological disturbances (the aura) that
usually precede the headache phase of an attack.
The pathogenesis and pathophysiology of migraine are
poorly understood. A diverse group of variables have been
implicated in the pathophysiology of migraine, in
particular, the serotoninergic system, with drugs that release
serotonin shown to precipitate migraine attacks , while
drugs that interact with serotonin receptors have
beneficial prophylactic and abortive effects . Glutamate,
which is a major excitatory neurotransmitter in the central
nervous system, has also been broadly involved in
migraine pathophysiology. Altered glutamate levels have
been measured in migraine patients  and glutamate has
been implicated in trigeminal activation and cortical
spreading depression (CSD), . In fact, stimulation of
the trigeminovascular system may be responsible for the
pain process during a migraine episode, whereas CSD
seems to underlie the aura symptoms . More
specifically, CSD activates the afferences from the trigeminal
system, which provokes an inflammation of meninges
underlying the pain and causing the headache .
Another neurotransmitter that plays an important role in
migraine pathophysiology, Gamma-aminobutyric acid
(GABA) . GABA, which acts mainly via GABA A and B
receptors, is the main inhibitory neurotransmitter in the
brain. Catecholaminergic, serotoninergic and
glutamatergic neurons are all under GABAergic inhibitory control.
GABAergic anticonvulsivant medications, are a first line of
therapy for prevention for migraine . Baclofen, a GABA
B analog, has also been shown to have an antinociceptive
effect in the central nervous system, and thus to be
efficient in the prophylaxis of migraine . Furthermore,
GABA A receptor agonists (Sodium valproate, gabapentin,
topiramate) are currently employed in preventing
migraine or reducing the frequency and the duration of
The GABA A receptor is a member of a superfamily
consisting of pentamers of homologous subunits arranged
around a central ion conducting channel (Cl- ions) .
There are 19 different subunit genes, divided into eight
subunit classes: 13, , 12, , , 16, 13, . GABA
A receptors are the targets of sedating drugs, such as
benzodiazepines, barbiturates, neurosteroids, and ethanol
While the mode of transmission of migraine is broadly
believed to be multifactorial, a role for a major
susceptibility gene has been postulated. In fact, migraine shows
strong familial aggregation. Approximately 50% of
migraine sufferers have an affected first degree relative,
with familial incidence figures varying from 61% to 90%
. Two Danish population based survey have provided
evidence to suggest that MA and MO may be two distinct
disorders with an independent genetic identity [16,17].
However, results of Australian  and Dutch  studies
have suggested that migraine with and without aura are
not etiologically distinct. It is most likely that there is at
least some shared genetic liability between the two
subtypes. Genetic characterization of the migrainous disorder
is making steady progress with an increasing number of
genomic susceptibility loci now identified on
chromosomes 1q, 4q, 5q, 6p, 11q, 14q, 15q, 17p, 18q, 19p and
Xq and more specifically in the Xq 2428 region [20,21].
This region contains a cluster of GABA A receptor subunit
(epsilon, alpha 3, theta) genes. A cluster of genes,
GABREGABRA3-GABRQ, spans a genomic region of about 700
Mb (figure 1); GABRE and GABRA3 genes encode for
epsilon and alpha3 subunits respectively and are transcribed
in centromeric direction, whilst the GABRQ gene encodes
for the theta subunit and is transcribed in telomeric
direction. Interestingly, studies performed in rat demonstrate
that these three subunits are co-expressed in specific brain
regions, in particular the locus caeruleus, with studies
demonstrating this may be involved in the migraine
In the present study, we investigated three Single
Nucleotide Polymorphisms (SNPs), previously described (rs
2050843 and rs 22566882 in GABRE gene and rs
3810651 in GABRQ) and a new mutation in exon 9 of the
GABRE gene, which has been recently identified by
sequencing. These polymorphism studies were
undertaken in a large Australian population of unrelated
subjects involving 275 migraineurs and 275 matched
A cross-sectional association approach was employed,
utilizing genomic DNA samples obtained from 275 migraine
affected individuals and 275 controls. The populations
consisted of Caucasians from the general Australian
Community. Before commencing the study, ethical clearance
was sought and approved by Griffith University's Ethics
Committee for Experimentation on Humans. Individuals
for the study were recruited from the local general
popuSFcigheumreat1ization of the location of the 4 studied SNPs on the chromosome X (q28)
Schematization of the location of the 4 studied SNPs on the chromosome X (q28). Pro 437 Leu is a new variation
identified by sequencing of exon 9 of GABRE gene.
lation using advertising via notices at Doctors Surgeries
and in Pharmacies, as well as through media release on
local radio, television and in press articles. Potential
participants contacted the Genomics Research Centre and
suitability for inclusion in the study was determined using
a detailed questionnaire completed by all participants,
providing demographic parameters, ancestry information
and family medical history. The control group consisted
of individuals with no family history of migraine.
Volunteers who did not meet these criteria were not included in
the study. All recruited individuals for the study gave
informed consent and were adult (18 years or older)
Caucasians of European descent living in Australia, having
emigrating ancestors within the last 160 years from
various locations within the British Isles and other parts of
Europe. In total ~600 cases and an equivalent number of
controls were collected over several years, with a random
275 cases and 275 matched controls used routinely for
our genotyping studies, and other samples set aside for
future independent studies. Samples used for the
genotyping studies were all individuals, not families, with care
taken not to include any related individuals in the
casecontrol population. Case and control individuals were
recruited from in and around the South Eastern Australia
Region, with collections undertaken in the Genomics
Research Centre Clinic at the Gold Coast, Queensland,
Australia. To minimize potential bias from population
stratification, the control group was matched for sex, age
(+/- 5 years) and ethnicity. Migraine patients were
clinically defined and suitably matched with non-migraine
individuals who made up the control population. The
subjects were diagnosed for migraine by a clinical
neurologist using a detailed questionnaire in accordance with
the International Headache Society criteria . Questions
used to define migraineurs included length and frequency
of attack; pain location, type and intensity; associated
symptoms such as nausea, vomiting, phonophobia,
photophobia and other visual disturbances, and other
neurological symptoms. All individuals were grouped together
and phenotyped as being affected with typical migraine
(MA+ MO = Migraine), as well as being diagnosed
separately as MA or MO subgroups. The blood samples
obtained from patients were collected through the
Genomics Research Centre patient clinic and purified
DNA from these samples was obtained using standard
extraction methods. Around 90% of the examined DNA
samples gave good genotyping results for the 4 selected
genetic markers. We excluded the samples with unclear
genotyping results. The study protocol was approved by
Griffith University's Ethics Committee for
Experimentation on Humans.
The study investigated three different polymorphisms at
the GABRE gene locus. The first marker was located in
exon 3 of GABRE and named GABRE 3 for the study.
GABRE 3 is a non synonymous SNP (ref database, rs
2050843) at position 102 (GT). PCR reactions (10l
final volume) containing 2 mmol/L MgCl2, 0.8 mol/L of
each primer, 200 mol/L dNTPs, 1 unit of Taq polymerase
and approximately 20 ng of genomic DNA were
undertaken for genotyping purposes.
Anti sense: 5'-AAATCCCTTTCTCCCTCCAG-3'
Thermal cycling was performed with an initial
denaturation of 60 seconds at 94C, followed by 35 cycles of 30 sec
at 94C, 30 sec at 58C, 30 sec at 72C, and a terminal
extension of 10 min at 72C. PCR products were then
digested with Bgl II and analyzed by electrophoresis on
4% agarose gels. Ethidium bromide stained gels were
digitally imaged and manually scored for genotypes. The PCR
products were 327 bp in size. The GABRE 3 G alleles did
not digest with Bgl II, whereas T alleles digested to give
177 bp and 150 bp fragments.
The second marker was a synonymous SNP (ref SNP
database, rs 2256882) at position 193 (C T) in exon 5,
named GABRE 5. PCR reactions and thermal cycling
conditions were the same as those cited above.
Anti sense: 5'-TGGCAGGAAAGGAAATGAGG-3'
To detect this SNP, PCR products were digested with Hpa
II and analyzed by electrophoresis on 4% agarose gels.
Ethidium bromide stained gels were digitally imaged and
manually scored for genotypes. The PCR products were
323 bp in size. The GABRE 5 T alleles did not digest with
Hpa II, whereas C alleles digested to give 180 bp and 143
The last marker for GABRE gene was a new variation
identified by sequencing exon 9 and identified at position 437
(C T), as a non synonymous SNP named GABRE 9. PCR
reactions were again the same as those cited above.
Anti sense: 5'-AGAGGGGCAGCAAAGACAAA-3'
Thermal cycling was performed with an initial
denaturation of 60 seconds at 94C, followed by 35 cycles of 30 sec
at 94C, 30 sec at 60C, 30 sec at 72C, and a terminal
extension of 10 min at 72C. PCR products were then
digested with Ava II and analyzed by electrophoresis on
2.5% agarose gels. Ethidium bromide stained gels were
digitally imaged and manually scored for genotypes. The
PCR products were 683 bp in size. The GABRE 9 T alleles
did not cut with Ava II and gave three fragments of 372 bp,
190 bp and 121 bp, whereas C alleles gave 301 bp, 190
bp, 121 bp and 71 bp fragments.
The last marker studied was a synonymous SNP (ref SNP
database, rs 3810651) at position 1432 (A T) in exon 9
of GABRQ gene, named GABRQ. PCR amplicons of 300
500 nt containing the 5' prime region and all 9 exons of
the GABRQ gene, including intron/exon boundaries, were
designed using the Oligo 4.0 software.
Anti sense: 5'-TTCGACACGGTTGCGGATTT-3'
PCR conditions were as follows; 1.5 mM of MgCl2, 1
standard PCR buffer, 0.2 mM of dNTPs, 0.5 M each of
forward and reverse primers, 1 unit of Taq polymerase, 40
ng of genomic DNA, mixed to final volume of 25 l with
sterile distilled water. The thermal cycle parameters
included: 1 cycle at 95C for 3 min for an initial
denaturation, followed by 35 cycles of denaturation for 30 sec at
94C, primer annealing for 30 sec at TM, primer
extension for 45 sec at 72C and a final extension for 10 min at
72C. Samples were then exosap digested (Amersham)
and sequenced using the Big Dye Terminator Ready
Reaction Kit (Applied Biosystem). Sequencing reactions were
performed on a 9700 Thermal Cycler (Applied
Biosystems) for 25 cycles of 95C for 10 sec, TM for 5 sec and
60C for 2 min. After the sequencing, each reaction was
column purified (Amersham) to remove excess dye
terminators. Sequencing of the products was performed on the
ABI prism 3100 Genetic Analyser (Applied Biosystems).
Polymorphisms were detected by multiple alignments of
sequences using the program Autoassembler (Applied
To detect association between each marker and migraine,
we performed chi-square (2) analysis to test for
significant differences in allele and genotype frequencies in case
versus control results . 2 provides the likelihood of a
deviation in the distribution of the same attributes in
different classes (e.g. allelic frequencies in controls versus
affected subjects). If the probability (P-value) of an equal
distribution between the two groups is below a
determined significance level (in percent), the statistical
output will show enough significance to assume LD and
We performed 2 analysis for MA, MO and combined
migraine groups versus control subjects for the GABRE 3,
5, 9 and GABRQ polymorphisms. We also tested for
linkage disequilibrium between tested markers using
Pearson's test to analyze dense genetic maps . The R2 value
0.0 suggests independent assortment, whereas 1.0 means
that all copies of the rarer allele occur exclusively with one
of the possible alleles at the other marker .
In total, we compared each of the three markers in
controls with three different case groups of the population
(MA, MO, Migraine (MO+MA)). Results were also tested
for Hardy-Weinberg Equilibrium (HWE) investigating
genotype frequencies of the studied markers to detect a
deviation from the normal genotype distribution in the
population and odds ratios were calculated to characterize
the distribution of distinct genotypes in different
phenotypic subgroups of the population. A priori power analysis
suggested that if any of the GABRE polymorphisms were
to confer an 2-fold or greater difference in odds for
migraine the total case and control groups used in this
study were of sufficient size to have >90% power to detect
an allelic association and >80% power to detect a
genotypic association at the 0.05 level.
This research was reviewed and approved by the Griffith
University Human Research Ethics Committee (ethics
protocol number MSC/05/05/HREC) and all subjects
participating in the study gave informed consent.
Three markers located within 15 kb of the coding region
of the GABRE gene and a marker in the GABRQ gene were
analyzed for association with migraine in a large
population (275 migraineurs versus 275 healthy individuals) of
Australia Caucasians. The distribution of GABRE 3, 5, 9
and GABRQ genotypes in the studied population did not
deviate significantly from Hardy-Weinberg Equilibrium
(P > 0.05).
Table 1 represents the results of the allelic and genotypic
frequency distribution of GABRE 3. There was no
significant association between both allelic and genotype
frequencies of GABRE 3 and migraine (2 = 0.33, P = 0.56
and 2 = 0.73, P = 0.695 respectively). Also, allelic
frequencies in control groups (pG = 0.762 and pT = 0.23) are
comparable to the frequencies reported previously in a
Caucasian population (pG = 0.692 and pT = 0.308) .
As shown in Table 1, the synonymous GABRE 5 marker
distribution for allelic and genotype frequencies did not
present significant association for migraine (2 = 0.57, P =
0.45 and 2 = 0.95, P = 0.62 respectively for allelic and
genotype frequencies). Similarly to the previous marker,
the allelic frequencies for GABRE 5 found in our
population (pC = 0.88 and pT = 0.12), are similar to prior reports
(pC = 0.91 and pT = 0.08) in a European population .
The analysis of the non synonymous GABRE 9 marker
also did not show any significant association with
migraine (2 = 0.76, P = 0.37 and 2 = 1.16, P = 0.56
respectively for allelic and genotype frequencies).
Stratified analyses of migraine subtypes was also
undertaken but did not indicate any association specifically
attributed to the MA or MO subtype group for either
allelic or genotypic frequencies for all of the three studied
SNPs (P > 0.05). Similarly, when we analyzed by gender,
no significant association was observed for the three
GABRE genotype and allelic distributions (P > 0.05) (cf.
Statistical analysis of the GABRQ variant revealed no
significant difference between genotyped migraineurs and
the matched control group in relation to genotype
frequencies (2 = 0.57, P = 0.753) and allele frequencies (2
= 0.19, P = 0.664) (cf. Table 2). Furthermore, no
significant difference was seen when the migraine population
was subdivided into MA and MO compared to control
group for both allelic and genotypic frequencies (P >
0.05), although the increased frequency of the TT
genotype in MO (27%) compared to MA (20%) may warrant
follow-up in a larger study group. The results were also
not statistically different between the migraine and
control groups regarding the gender (P > 0.05). With regard to
male allele frequencies, it was however interesting to note
a higher frequency of the T allele in male MO migraineurs
(60%) compared to the male MA migraineurs (41.2%)
and the male control group (44.1%).
Linkage disequilibrium analysis was also undertaken
between the 3 GABRE and GABRQ markers. The analysis
of LD between the GABRE markers revealed a moderate
but significant linkage disequilibrium between GABRE 5
and GABRE 9 (R2 = 0.38, P = 0.00001). However, this LD
value decreased by more than 30% and become non
significant (P 0.05) when measured between GABRE 3 and
GABRE 5 on one hand, and GABRE 3 and GABRE 9 on the
other hand (cf. Table 3). The analysis of LD between the 3
GABRE markers and GABRQ did not show any significant
linkage disequilibrium (P > 0.05) (cf. Table 3).
A substantial body of literature suggests that GABA may be
involved in the neuropathophysiology of migraine yet
there have been few studies investigating GABA receptor
genes as potential candidate genes for migraine. -Amino
butyric acid (GABA) is the major inhibitory
neurotransmitter of the brain, occurring in 3040% of all synapses in
regions such as the cerebral cortex, hippocampus,
thalamus, basal ganglia, cerebellum, hypothalamus and
brainstem . -Amino butyric acid type A (GABA A)
receptors are the major sites of fast synaptic inhibition in
the brain and are also the sites of action for many
psychoactive drugs including the benzodiazepines and
barbiturates . In mammals, they are constructed as
pentameric structures from multiple subunits selected
predominantly from the following distinct classes: (1
6), (13), (13), , , and , creating an incredible
(165) potential for structural diversity. Studies have
demonstrated that the subunit combination determined the
Table 2: Distribution of the GABRQ gene exon 9 variation (P437I) in migraineurs and controls of original sample (MO migraine
without aura, MA migraine with aura).
affinity for GABA and the specific effects of allosteric
Recently, new members (epsilon and theta) of the GABA
A receptor gene family have been discovered [30-32]. It is
worth noting that alpha3-, theta- and epsilon-subunits are
clustered on the X-chromosome  and that functional
expression of recombinant receptors, as well as amino
acid sequence identity analysis, have suggested that
thetaand epsilon-subunits may substitute for beta- and
gamma-subunits, respectively [33,34].
Functional expression of recombinant subunits has
indicated that, in some brain areas (i.e. locus caeruleus, dorsal
raphe, and hypothalamus) already demonstrated to be
potentially involved in the migraine disorder, the theta
subunit is co-expressed with epsilon and alpha3 subunits,
suggesting that these subunits are associated in some
native GABA A receptors .
In this study, we analyzed the distribution of genotype
and allele frequencies of three SNPs located in the GABRE
gene and one variant in the GABRQ gene in a large
population of migraineurs and matched controls. Three of
these markers are non synonymous SNPs (GABRE 3,
GABRE 9 and a new variation in GABRQ) and induce
changes of amino acids in the protein receptor (Ala102Ser
and Pro437Leu, Ile478Phe respectively). The last SNP
studied was synonymous (Ala193Ala), located in exon 5
of the GABRE gene (GABRE 5).
The study did not find any association between the three
analysed SNPs in the GABRE gene and migraine. The
GABRE gene contains 9 exons, which code for 4 different
variants of GABRE . The role of this splicing remains
unclear at present. The first variant is a the full-length
functional transcript and is highly expressed in heart and
lung and also present in brain [37,38]. In variant 2, exons
13 are spliced out, and in variant 3 the same splicing
occurs in combination with a deletion of residues 127
158 from the centre of exon 4 . The mRNAs of variants
2 and 3 have been found in several peripheral tissues .
In variant 4 only exon 1 is deleted. Variants 2, 3 and 4 lack
the signal peptide and also (for forms 2 and 3) lack a
significant region of the extracellular N-terminal domain,
* Correlation is significant at the 0.05 level.
** Correlation is significant at the 0.001 level
but the roles for these variants (form 2, 3 and 4) in
combination with the full-length variant 1 remain unclear.
Our results also did not show any association between the
tested GABRQ marker (rs 3810651) and migraine. No
significant association was reported for both MA and MO
populations for the studied single missense variation,
A1432T. Of interest is the frequency distribution of the T
allele in male MO (60%) patients versus male MA patients
(41.2%) and versus male controls (44%). While this
analysis did not reach statistical significance, due to small
numbers in the male subgroup, it may warrant further
investigation in a larger study group. The A1432T
variation altered a conserved amino acid; the isoleucine amino
acid is conserved in primate and mouse. The functional
significance of the isoleucine residue in codon 478 is
unknown but the high degree of conservation across
several species argues strongly in favor of an important role
of this amino acid in the function of GABRQ protein. The
hypothesis that the isoleucine residue in codon 478 may
constitute an important point for GABRQ function, which
would be perturbed (pathogenic) by the phenylalanine
substitution, should be considered.
Previous linkage studies in our research group have
reported mapping of a migraine gene to the X
chromosome in three large Australian pedigrees [20,39].
Although results from haplotype and linkage analyses
(employing 28 markers spanning the entire X
chromosome) localized the disease locus in the Xq 2428 region,
these findings may be specific to the studied population,
which may not be representative of the general
The GABA neurotransmitter has been previously
implicated in the pathophysiology of migraine, but there have
been only recent studies in migraine genetics. Russo et al.
reported significant linkage, in five Italian families
suffering from a migraine subtype with the 15q11q13
chromosomal region, a region containing clusters of GABA A
receptor subunit (beta 3, alpha 5 and gamma 3) genes
. More studies need to be undertaken and in
particular, on other genetic markers in the other GABA receptors
genes present in the Xq28 gene cluster. The GABA A
receptor subunit alpha 3 (GABRA3) gene is also located in this
region. A dinucleotide cytosine-adenosine repeat
polymorphism with 6 alleles representing 11 to 16 repeats has
been described by Hicks (2000) in the GABRA3 gene .
This polymorphism has been associated with Multiple
Sclerosis , but also with Bipolar Disorder [43,44].
Both of these neurological disorders shared a comorbidity
with migraine . A GABRA3 microsatellite has been
also studied in another psychiatric disorder population
(suicide attempts) but no significant association has been
reported for this genetic marker .
GABA levels in the cerebro-spinal fluid of patients during
a migraine attack have been reported to be higher
compared to the levels measured during a headache free
period in the same individuals . Kowa et al. (1992),
have also observed higher GABA levels in blood platelets
of patients suffering from tension headache .
Furthermore, the GABAergic migraine prophylactic drugs may
restore a normal cortical inhibitory potential by elevating
cortical threshold for spreading depression propagation
in patients with migraines . GABA neurotransmitter
plays a key part in cerebral physiology, and is able to
inhibit a number of neurohormones including serotonin,
catecholamines and glutamate. Like other ligand gated
ion channels, such as the GABA A receptor, the ionotropic
glutamate receptor subunits possess four subunits. The
ionotropic glutamate receptor, AMPA-selective glutamate
receptor 3, has been located to the Xq 2428 region,
mapped migraine susceptibility .
Previous studies in our laboratory have reported
significant evidence for the location of a migraine susceptibility
locus on chromosome Xq  and more specifically to
the Xq 2428 region . Previous candidate genes
5HT2C receptor gene, residing in this region have not
revealed genetic differences between migraineurs
compared to controls [51-53]. Also, lack of association of
Monoamine Oxidase genes located on chromosome X,
with migraine susceptibility has been reported in several
studies [54-56]. Chromosome X studies and migraine
susceptibility have been investigated for the last decade. The
prevalence of migraine in children before puberty has
been reported to be quite similar in boys and girls (4%)
 but migraine occurs more frequently in adult women
(18%) than in men (6%) . GABAergic neurons are
strongly modulated by ovarian hormones with studies
showing an effect of estrogen and progesterone and its
metabolites on GABA receptors [59-61], as well as cortical
GABA levels . Although this study has not implicated
tested markers in the GABRE gene, further investigation of
other GABA related genes, particularly in the cluster of
GABA A receptor subunit genes residing at Xq 2428
region, is required to define their potential role in
The authors declare that they have no competing interests.
FF and TE were responsible for undertaking all the
experiments and the analysis of data was undertaken
collaboratively by all authors. LG coordinated the study and revised
the manuscript. All authors read and approved the final
This work was supported by funding from an ARC Linkage and an NHMRC
Grant from Australia
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