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. Author manuscript; available in PMC: 2011 Aug 1.
Published in final edited form as: Genes Brain Behav. 2010 Jun 18;9(6):668–672. doi: 10.1111/j.1601-183X.2010.00598.x

Association of the GABRD Gene and Childhood-Onset Mood Disorders

Yu Feng 1, Krisztina Kapornai 2, Eniko Kiss 2, Zsuzsa Tamás 3, László Mayer 2, Ildikó Baji 3, Gabriella Daróczi 2, István Benák 2, Viola Osváth Kothencné 2, Edit Dombovári 2, Emília Kaczvinszk 2, Márta Besnyő 3, Julia Gádoros 3, Judit Székely 5, Maria Kovacs 6, Ágnes Vetró 2, James L Kennedy 4, Cathy L Barr 1,7
PMCID: PMC2935687  NIHMSID: NIHMS208145  PMID: 20561060

Abstract

The chromosome 1p36 region was previous indicated as a locus for susceptibility to recurrent major depressive disorder based on a linkage study in a sample of 497 sib pairs. We investigated the GABAA δ receptor subunit gene, GABRD, as a susceptibility gene to childhood-onset mood disorders (COMD) because of substantial evidence implicating GABAergic dysfunction in mood disorders and the position of this gene near the 1p36 linkage region. Using a sample consisting of 645 Hungarian families with a child/adolescent proband diagnosed with a mood disorder with the onset of the first episode before age 15, we found some evidence for association of two polymorphisms located within the gene, rs2376805 and rs2376803, as well as significant evidence for biased transmission of the haplotypes of these two markers (global χ2 test for haplotypes = 12.746, 3df, p=0.0052). Further, significant evidence of association was only observed in male subjects (n=438) when the results were analyzed by sex (χ2 =9.000, 1df, p=0.003 for rs2376805). This was in contrast with the previous linkage findings, as LOD scores exceeding 3 were only in female-female pairs in that study. These findings point to the GABRD gene as a susceptibility gene for COMD, however, this gene may not explain the previous linkage finding.

Keywords: GABRD, child, depression, genetics, mood disorders, GABA, GABA receptors, chromosome 1p

Introduction

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain, has been implicated in the pathogenesis of mood disorders based on several lines of evidence including low cerebrospinal fluid and plasma levels of GABA, and more recently proton magnetic resonance spectroscopy indicating low GABA concentrations in the occipital cortical and prefrontal regions (Berrettini et al., 1983, Petty et al., 1993, Sanacora et al., 2004, Krystal et al., 2002, Brambilla et al., 2003, Tunnicliff and Malatynska, 2003, Hasler et al., 2007). The GABA A receptors (GABAARs) are constructed from a large number of possible subunits with different subunit compositions providing different physiological and pharmacological functions which contribute to the heterogeneous roles of GABAA receptors in the mammalian brain (Mohler, 2006, Jacob et al., 2008). The majority of GABAA receptors are composed of two α subunits, two β, and one γ or δ subunit. Those composed of α4 or α6 subunits together with β and δ subunits are predominantly located at extrasynaptic sites and mediate tonic inhibition in the brain (Mohler, 2006). The δ subunit is highly expressed in brain and expression has been reported in cerebellum, cerebral cortex, medulla, occipital pole, frontal lobe, temporal lobe and putamen (Windpassinger et al., 2002). Of the GABA receptors, the δ subunit-containing GABAA receptors are particularly implicated in mood disorders. These receptors have a high affinity for GABA and are the preferential targets of neuroactive steroids (Stell et al., 2003), which are endogenous steroids (progesterone, pregnenolone, 3α, 5α-tetrahydroprogesterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate) implicated in anxiety and depression (Eser et al., 2006, Longone et al., 2008).

Genetic studies also implicate the GABAergic system in mood disorders. The recently published Wellcome Trust Case Control Consortium (WTCCC) genome-wide association study for bipolar disorder found strong evidence that genetic variation in the GABAA receptor β1 subunit gene, GABRB1, influences risk for RDC schizoaffective disorder, bipolar type (Craddock et al., 2010). Further study of this specific clinical subtype in that sample identified association of the GABRA4, GABRB3, GABRA5 and GABRR1 genes. Previous to that study, a number of the GABA subunit genes had been investigated in linkage and association studies of unipolar and bipolar disorder with conflicting results (Brambilla et al., 2003). Sample size may be a factor in the conflicting findings for some of the studies, particularly for early studies.

The δ subunit encoded by the GABRD gene is a positional candidate, as well as a functional candidate based on the position of this gene in 1p36, a region with suggestive evidence for linkage with recurrent major depressive disorder (McGuffin et al., 2005). Association studies of the GABRD gene have not been reported to date. There were no genotyped markers in the GABRD gene in the WTCCC bipolar association study (Craddock et al., 2010), likely due to the small size of the gene (~11 kb), thus they were unable to test this gene in that sample.

Based on the biologic function of GABAergic systems in the pathogenesis of mood disorders, particularly the special role of the δ subunit in GABAA receptors and the linkage findings pointing to the 1p36 region, we investigated the role of the GABRD gene in childhood-onset mood disorders using a large family-based sample from Hungary. Our sample consisted of 645 nuclear families (807 affected children) with a proband diagnosed with a mood disorder with the onset of the first episode by age 15.

Subjects

The diagnostic assessment, inclusion/exclusion criteria and clinical characteristics of the families enrolled in this study have been published previously (Liu et al., 2006, Kiss et al., 2007, Kapornai et al., 2007, Tamas et al., 2007, Baji et al., 2009). Families were recruited from 23 mental health facilities across Hungary as part of a multidisciplinary Program Project to study risk factors in childhood-onset mood disorders (Liu et al., 2006). The probands were diagnosed using the Interview Schedule for Children and Adolescents - Diagnostic Version (ISCA-D), an extension and modification of the ISCA (Sherrill and Kovacs, 2000). Children and parents were interviewed separately and approximately one month later both were interviewed again by a different clinician (psychologist/psychiatrist). Children were interviewed about themselves and parents about their child’s symptoms. The final diagnosis was based on consensus among two independent child psychiatrists. The probands met DSM-IV criteria of a mood disorder (depressive or bipolar disorder), with the onset of the first episode by 14.9 years of age. For 14 of the siblings, who also were affected, onset of a mood disorder was between 15 and 18 years of age and they were diagnosed using the same procedure as with probands. This study met with IRB approval at the University of Pittsburgh, the Centre for Addiction and Mental Health, Toronto, and all recruitment centers in Hungary. Written informed consent was obtained from parent and child.

The analyses for this study were based on the genotypes of 645 families with 807 affected children (438 males, 369 females). At the time of diagnosis, 0.8% of the children met criteria for bipolar disorder. Given the young age of the children, we expect that 20 to 30% of those currently diagnosed with unipolar depression will develop bipolar disorder as they mature. Because it is not possible to predict which of these children will develop bipolar disorder, they cannot be excluded from our sample.

Genotyping

DNA was extracted from blood using a high salt method (Miller et al., 1988). The polymorphisms were genotyped using the TaqMan ® 5′ nuclease assay with primers and probes available commercially (Applied Biosystems, Foster, CA, TaqMan ® SNP Genotyping Assay). Five μl PCR reactions contained 30 ng of genomic DNA, 2.5 μl of 2 × TaqMan ® Universal PCR Master Mix (Applied Biosystems) and 0.125 μl of 40 × SNP genotyping assay mix which contained 36 μM of each primer and 8 μM of each probe. The thermal cycling conditions were 95°C for 10 min, then 40 cycles of 95°C for 15 seconds and 1 minute at the annealing temperature. Two negative controls were included for each 96 well plate. Plates were read on the ABI 7900-HT Sequence Detection System using the allelic discrimination end-point analysis mode of the software package version 2.0 (Applied Biosystems).

Statistical Analysis

All data were screened for Mendelian errors using PEDSTATS, and MERLIN to detect any crossovers between markers (Abecasis et al., 2002). This data set was free of any detectable Mendelian errors and none of the markers used deviated from Hardy-Weinberg Equilibrium (Table 1).

Table 1.

TDT results for single marker analyses

SNP ABI assay ID Allele HWpval Freq. Trans Not Transmitted χ 2 p value (1df)
rs3795283 A 1.00 0.333 231 252 0.913 0.339
rs2376805 C_16000020_10 G 0.33 0.189 147 193 6.243 0.012a
rs2376803 C_16000021_10 C 0.47 0.312 208 258 5.375 0.020
rs7513222 C_30490003_10 A 0.43 0.348 242 250 0.130 0.718
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a

1000 permutations were performed using UNPHASED on the best p value to correct for the number of tests (global significance: p=0.062; SE=0.008). HWpval indicates the p value for the test of Hardy-Weinberg Equilibrium.

The TDTPHASE program of the UNPHASED package was used to test for biased transmission of alleles (Dudbridge, 2003). Association of haplotypes was evaluated using TRANSMIT with the robust estimator option (Clayton and Jones, 1999). Haplotypes with frequencies less than 10% were pooled and χ2 and p values are only reported for those with frequencies greater than 10%. The degree of linkage disequilibrium (LD) between markers was evaluated using Haploview v3.2 (http://www.broad.mit.edu/mpg/haploview) (Barrett et al., 2005) (Table 2).

Table 2.

Linkage Disequilibrium between Markers

rs3795283 rs2376805 rs2376803 rs7513222
rs3795283 0.159 0.036 0.101
rs2376805 0.003 0.915 0.076
rs2376803 0.001 0.434 0.077
rs7513222 0.003 0.003 0.001
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Upper right shows the degree of linkage disequilibrium between markers as measured by D’ and the bottom left as measured by r2

Results

Since few polymorphisms have been validated in the GABRD gene, there were no tag SNP markers identified within the gene in HapMap that could be used for this study. The 4 polymorphic SNPs in HapMap, all located in intron 1 had the same minor allele frequency, indicating strong linkage disequilibrium (LD). We selected four informative SNP markers across the gene to genotype, two were within the gene region (rs2376805 located in intron 1 and rs2376803 3′ to the gene, 5.8 kb from the coding region), one was located at the far 5′ side (rs3795283, 34 kb from the coding region) and the other was located 3′ to the gene (rs7513222, 66 kb from the coding region). We further genotyped a reported, but not validated, non-synonymous SNP rs28753776 (Thr161Ser) on the sample but did not find any evidence for variation in the DNA of 188 individuals tested.

The single marker TDT analysis for the four polymorphic markers is shown in Table 1. The two SNPs within the gene region exhibited biased transmission of alleles to the affected offspring, rs2376805 and rs2376803. Permutation analysis was performed on the TDT analysis. The best p value (p=0.012) however was no longer significant after correcting for the number of markers (p=0.062).

We examined the LD between the markers (Table 2) and observed LD only between the two markers within the GABRD gene region (rs2376805 and rs2376803). We performed haplotype analysis using these two markers and observed significant biased transmission of haplotypes to the affected children. One common haplotype with frequency 68.5% was over-transmitted to affected offspring (χ2 =11.495, 1df, p=0.0007) while another common haplotype with frequency 17.5% was less often transmitted to the affected children (χ2=8.16, 1df, p=0.0043), with a global value of χ2=12.746, 3df, p=0.0052 (Table 3).

Table 3.

Haplotype analysis of the two markers in LD

rs2376805 rs2376803 Frequency Observed Expected Var(O-E) χ 2 p value (1df)
A C 0.131 183.39 193.27 81.01 1.203 0.2727
G C 0.175 234.60 262.97 98.67 8.160 0.0043
A T 0.685 1073.60 1032.30 148.68 11.495 0.0007
G T 0.009
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Global chisquared test for haplotypes with frequencies greater than 10% = 12.746, 3df, p=0.0052

As the previous linkage study only observed evidence for linkage on chromosome 1p36 in female-female pairs (McGuffin et al., 2005), we stratified our sample by sex and examined the transmissions to female (n=369) and male (n=438) children separately for the analysis of single markers (Table 4) and haplotypes (Tables 5 and 6). Significant evidence of association was only observed in male subjects (Tables 4 and 5). This contrasts to the findings from the linkage study that found evidence for linkage only in females (McGuffin et al., 2005).

Table 4.

TDT Analyses by Sex of the Child

rs2376805 (G allele) rs2376803 (C allele)
Freq Trans Not
Trans		 χ 2 p value
(1df)		 Freq Trans Not
Trans		 χ 2 p value
(1df)
females 0.190 70 74 0.111 0.739 0.314 96 100 0.082 0.775
males 0.183 77 119 9.000 0.003 0.305 112 158 7.837 0.005
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Table 5.

Haplotype Analyses for Males

rs2376805 rs2376803 Frequency Observed Expected Var(O-E) χ 2 p value (1df)
A C 0.124 95.12 101.08 43.91 0.808 0.3687
G C 0.173 116.88 141.82 55.33 11.243 0.0008
A T 0.696 595.88 563.74 81.29 12.711 0.0004
G T 0.006
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Global chisquared test for haplotypes with frequencies greater than 10% = 14.517, 3df, p=0.0022

Table 6.

Haplotype Analyses for Females

rs2376805 rs2376803 Frequency Observed Expected Var(O-E) χ 2 p value (1df)
A C 0.133 79.21 85.75 34.82 1.229 0.2676
G C 0.167 109.79 111.83 40.05 0.104 0.7471
A T 0.686 465.79 455.68 64.09 1.595 0.2066
G T 0.013
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Global chisquared test for haplotypes with frequencies greater than 10% = 2.215, 3df, p=0.5290

Discussion

In this study we investigated the GABRD gene based on substantial evidence for GABA dysfunction in mood disorders and the position of the gene near the region linked with recurrent depressive disorders. We found evidence for association between genetic markers in the GABRD gene and COMD, with haplotypes significantly biased in transmission. Further, the association appeared to be sex specific; being restricted to the males in the sample. These results, particularly, the significant results from haplotype analyses, indicate that genetic variation in the GABRD gene could contribute to the linkage signal in the 1p36 region reported in a previous genome scan for recurrent depressive disorders. However, the results were only significant in males, in contrast to the previous linkage findings.

While sex appears to be a factor in the association of GABRD in our study and the previous linkage study, it’s not clear why the findings are in opposite directions. This discrepancy could be explained in the linkage study by the small number of male-male pairs (58 compared to 266 female pairs) with low power on their own to detect an effect. However, it does not explain the LOD score in the female pairs (3.03 in females compared to 1.9 in the entire sample and −0.08 in males).

Phenotype may also be a factor in the discrepant findings. Our sample was composed of childhood and adolescent probands with the onset of the first episode by 15 years old (mean age of first onset 10.8 years, S.D. 2.28). There is some evidence that earlier age of onset may have unique genetic risks. A recent large twin study of depressive and anxiety symptoms in children and adolescents at ages 8-9, 13-14, 16-17, and 19-20 supports a common genetic factor across these ages as well as unique genetic contributions at each age point (Kendler et al., 2008). Both genetic innovation (new genes that were previously without effect on the phenotype become active) and attenuation (genes that impact at one developmental age that decline in their influence during subsequent periods) were supported across these age groups. Although not significant, there was also evidence that the genetic correlation between males and females decreased with increased age, indicating the possibility of sex specific differences in genetic risk at different ages. Thus, age, and sex related specific genetic risks should be considered as a possible explanation. Alternatively, the association in GABRD detected here may not be contributing to the linkage signal. That paper describes the peak location as 13.8 to 21.8 cM corresponding to ~7.2 to 14.5 Mb on Build 35. This would be greater than 5 Mb centromeric to GABRD located at 1.99 Mb. Studies of this gene in the linkage sample of families would be optimal and replication in independent samples is of course required before any conclusions can be made.

Interestingly, there are some data indicating a role of the δ receptor in pubertal anxiety in females (Shen et al., 2007). The neurosteroid allopregnanolone (TPH), released in response to stress, has been shown to increase anxiety like behavior in pubertal mice in contrast to an anxiety-reducing effect in pre-pubertal and adult mice (Shen et al., 2007). Studies indicate that the effects of TPH reverse from enhancing GABA-gated current at α4β2δ receptors to inhibiting current in a Cl− -dependent manner. Specifically implicating the δ subunit was the finding of up to two fold increased expression of this subunit in the CA1 hippocampus region of mice at the onset of puberty. Thus sex and developmental influences on the expression of this gene may contribute to the finding of association only in males in this age group.

Twin and family studies indicate that mood disorders are complex, with multiple genes involved, and any one gene will be unlikely to have a large contribution to risk. Association studies now point to a few candidate genes with support from multiple studies (Craddock and Forty, 2006). Here we report evidence for the GABRD gene as associated with childhood-onset mood disorders. Our finding, in conjunction with the recent reported association findings for the GABA subunit genes reported in the whole genome associations studies, indicate a substantial role of GABA dysfunction in the pathogenesis of mood disorders. DNA variants in the GABRD gene could modify gene expression or function and hence, affect the subunit composition and the physiological and pharmacological properties of the GABAA receptors. Further work should address the functional DNA changes in the gene and investigate the mechanisms behind the observed sex specific effect.

Acknowledgements

The National Institute of Mental Health Program Project grant, MH 56193 and the National Alliance for Research on Schizophrenia and Depression, supported this work.

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