GABRG1 and GABRA2 as Independent Predictors for Alcoholism in Two Populations

Abstract

The chromosome 4 cluster of GABA A receptor genes is predominantly expressed in the brain reward circuitry and this chromosomal region has been implicated in linkage scans for alcoholism. Variation in one chromosome 4 gene, GABRA2, has been robustly associated with alcohol use disorders (AUD) although no functional locus has been identified. As HapMap data reveal moderate long-distance linkage disequilibrium across GABRA2 and the adjacent gene, GABRG1, it is possible that the functional locus is in GABRG1. We genotyped 24 SNPs across GABRG1 and GABRA2 in two population isolates: 547 Finnish Caucasian men (266 alcoholics) and 311 communityderived Plains Indian men and women (181 alcoholics). In both the Plains Indians and the Caucasians: (1) the GABRG1 haplotype block(s) did not extend to GABRA2; (2) GABRG1 haplotypes and SNPs were significantly associated with AUD; (3) there was no association between GABRA2 haplotypes and AUD; (4) there were several common (X0.05) haplotypes that spanned GABRG1 and GABRA2 (341 kb), three of which were present in both populations: one of these ancestral haplotypes was associated with AUD, the other two were more common in non-alcoholics; this association was determined by GABRG1; (5) in the Finns, three less common (o0.05) extended haplotypes showed an association with AUD that was determined by GABRA2. Our results suggest that there are likely to be independent, complex contributions from both GABRG1 and GABRA2 to alcoholism vulnerability.

Association of Gamma-Aminobutyric Acid A Receptor α2 Gene (GABRA2) with Alcohol Use Disorder

“…One study (Lind et al, 2008) was excluded because it investigated families comprised of monozygotic and dizygotic twin pairs; one study (Khan et al, 2009) was excluded because the definition of alcoholism was based on alcohol consumption only; and four studies (Agrawal et al, 2006;Dick et al, 2005Dick et al, , 2006Edenberg et al, 2004) were excluded because the data were not made available after we contacted the authors to request access to the data. In the end, 27 studies (Chang et al, 2002;Covault et al, 2004Covault et al, , 2008Enoch et al, 2009;Fehr et al, 2006;Foley et al, 2004;Han et al, 2008;Hsu et al, 1998;Lappalainen et al, 2005;Li et al, 2002;Lin et al, 2003;Loh et al, 1999Loh et al, , 2000Loh et al, , 2007Lydall et al, 2011;Nishiyama et al, 2005;Onori et al, 2010;Park et al, 2006;Sander et al, 1999;Soyka et al, 2008) met our criteria for inclusion (Supplementary Table 3). These studies included a total of 4739 cases (AD, HD, or MD) and 4924 controls.…”

“…Moreover, although other GABA receptor genes have been proposed to be associated with drug or AD, there were not sufficient published data on them for meta-analysis. For example, we only analyzed the GABRA2 gene on chromosome 4p12, but not its adjacent gene, GABRG1, because of insufficient genetic data available for a meta-analysis although GABRG1 has also been reported to be associated to AD Edenberg et al, 2004;Enoch et al, 2009;Ittiwut et al, 2012). In addition, in this meta-analysis most original association studies had no information on comorbidity in their research subjects, which made it impossible for us to address some other interesting issues, such as whether an observed association with one substance might be driven by another.…”

“…For instance, markers in the 3' region of GABRA2 are in LD with markers at the adjacent GABRG1 Ittiwut et al, 2008). It is possible that the association identified in GABRA2 has a component because of LD with GABRG1, with risk loci in both genes Enoch et al, 2009). In this meta-analysis, we analyzed all the functional receptor genes with available genotype data sets sufficient for metaanalyses (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12).…”

Hyposensitivity to Gamma-Aminobutyric Acid in the Ventral Tegmental Area During Alcohol Withdrawal: Reversal by Histone Deacetylase Inhibitors

“…The b3 subunit may be particularly important for GABA-A receptor trafficking and control of responsiveness to GABA (Parker et al, 2011). Furthermore, in humans, the genes encoding the GABA-A receptor subunits are clustered in several chromosomal regions, and the chromosome 4 clusters of genes are likely to be important in addiction and anxiety and may be vulnerable to epigenetic effects in early development (Enoch et al, 2009).…”

An Association Study of the COMT and GABA Gene Variants with Alcohol Dependence

“…Another gene cluster GABRG1, GABRA2, GABRA4 and GABRB1 is present on chromosome 4p12 [19,20]. Several genetic studies, including association and genome-wide association studies, implicate various GABA receptor genes as AD susceptibility candidates [21][22][23][24][25][26][27][28][29][30].…”