Variations in GABRA2, Encoding the α2 Subunit of the GABAA Receptor, Are Associated with Alcohol Dependence and with Brain Oscillations

Abstract

Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13-28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P=.000000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.

GABRA2 Alleles Moderate the Subjective Effects of Alcohol, Which are Attenuated by Finasteride

“…In addition, all 3-SNP haplotypes examined in the 3 0 region of GABRA2 were significantly associated with alcohol dependence (Edenberg et al, 2004). Covault et al (2004) replicated this haplotypic association in a region of the gene that overlaps the region identified by Edenberg et al (2004). These findings, together with evidence that GABA A receptors mediate several behavioral effects of alcohol (Grobin et al, 1998;Davies, 2003), underscore the potential contribution of variation at GABRA2 to the risk for alcohol dependence.…”

“…The rs279858 SNP, which is a synonymous A-to-G substitution (K132K) in exon 4 of the GABRA2 gene, was genotyped using the TaqMan 5 0 nuclease assay with ABI Assay-onDemand #2073557. This SNP lies in the middle of the haplotype block in GABRA2 that was observed to be associated to alcohol dependence by Edenberg et al (2004) in a family-based study and by Covault et al (2004) in a case-control study. Although the G-allele of this SNP was less common overall, it was over-represented among alcohol-dependent individuals (Covault et al, 2004), and may therefore be considered a potential 'risk' allele.…”

“…Although the G-allele of this SNP was less common overall, it was over-represented among alcohol-dependent individuals (Covault et al, 2004), and may therefore be considered a potential 'risk' allele. Conversely, since the A-allele, although more common overall, was less frequently transmitted (Edenberg et al, 2004) among alcoholics or was over-represented among healthy controls (Covault et al, 2004), it may be considered a 'protective' allele.…”

“…A larger sample would make it possible to examine an additive effect of the alleles by using all three genotype groups to examine both the response to alcohol and its modification by finasteride. In addition, the functional effects of the allelic variation at GABRA2 are not understood (Edenberg et al, 2004;Covault et al, 2004), so that additional research is required to elucidate the potential mechanism by which the gene influences the response to alcohol.…”

“…Edenberg et al (2004), by fine mapping this region, found that numerous single-nucleotide polymorphisms (SNPs) in the gene encoding the GABA A a-2 subunit (GABRA2), but not in other members of the gene cluster, were associated with alcohol dependence. In addition, all 3-SNP haplotypes examined in the 3 0 region of GABRA2 were significantly associated with alcohol dependence (Edenberg et al, 2004). Covault et al (2004) replicated this haplotypic association in a region of the gene that overlaps the region identified by Edenberg et al (2004).…”