A GABRA2 variant is associated with increased stimulation and 'high' following alcohol administration

Abstract

Aims: Variation in genes encoding GABAA receptor subunits has been implicated in the risk of alcohol dependence (AD). We sought to replicate and extend previous findings of a moderating effect of single nucleotide polymorphisms (SNPs) in GABRA2 (which encodes the GABAA α-2 subunit) on the subjective effects of alcohol by examining SNPs in this and the adjacent GABRG1 gene on chromosome 4.

Methods: Fifty-two European-Americans (22 males, 28 light drinkers and 24 heavy drinkers) completed 3 laboratory sessions, during which they drank low-dose, high-dose, or placebo alcohol prior to undergoing periodic assessments of stimulation, sedation and drug enjoyment. We genotyped subjects for three SNPs previously associated with AD: rs279858 in GABRA2, and rs7654165 and rs6447493 in GABRG1.

Results: Two SNPs were associated with altered stimulatory effects of alcohol as measured on the Biphasic Alcohol Effects Scale, (rs279858: P = 0.0046; rs6447493: P = 0.0023); both effects were in the opposite direction of previous findings. Carriers of the rs279858 C allele experienced greater stimulation from alcohol. Further inspection of the rs6447493 interaction did not support a pharmacogenetic effect. The effects of rs279858 (but not the other two SNPs) on items from a secondary outcome measure, the Drug Effects Questionnaire (DEQ), were significant. Higher ratings by individuals with the C allele were observed on the DEQ items 'feel the alcohol effect' (P < 0.001), 'like the alcohol effect' (P < 0.001) and feel 'high' (P < 0.001).

Conclusion: We did not find that the GABRG1 SNPs rs7654165 and rs6447493 moderated the effects of alcohol. Greater stimulatory and euphoric effects of alcohol in carriers of the rs279858 C allele may, in part, explain the previously reported association of this allele with AD.

Fig. 1.

Timeline of events in the laboratory sessions. VS, vital signs (heart rate and blood pressure); BrAC, breath alcohol concentration; SRM, subjective response measures.

Fig. 2.

Mean breath alcohol concentration (BrAC) over time for women and men. The targeted BrAC was achieved, but with men averaging slightly higher BrACs than women.

Fig. 3.

Influence of the GABRA2 SNP rs279858 on Biphasic Alcohol Effects Scale (BAES) stimulation. A significant interaction was seen for alcohol dose by genotype (F(4,251) = 3.86, P = 0.0046). Subjects heterozygous and homozygous for the C allele showed a higher stimulatory response than the T-allele homozygotes following the high dose of alcohol. The results were also significant for a simplified model with the two-level genotype of ‘C-allele carrier.’

Fig. 4.

Influence of the GABRA2 SNP rs279858 on the Drug Effects Questionnaire (DEQ) item ‘feel the alcohol effect’. The interaction of dose by genotype was significant for the two-level genotype of C allele carriers (F(1,563) = 16.085, P < 0.001). Subjects having at least one of the C alleles reported greater ‘feel the alcohol effect’ following high-dose alcohol ingestion.

Fig. 5.

Influence of the GABRA2 SNP rs279858 on the Drug Effects Questionnaire (DEQ) item ‘like the alcohol effect’. A significant dose by genotype interaction (F(1,563) = 21.25, P < 0.001) was found for the two-level genotype variable of C allele carriers. Subjects having at least 1 of the C alleles reported greater ‘like the alcohol effect’ following high-dose alcohol ingestion.

Fig. 6.

Influence of the GABRA2 SNP rs279858 on the Drug Effects Questionnaire (DEQ) item ‘feel high’. The dose by genotype interaction was significant for the two-level genotype C allele carriers (F(1,563) = 13.08, P < 0.001). Subjects having at least 1 of the C alleles reported greater ‘feel high’ following high-dose alcohol ingestion.