In human association studies, variation in gamma amino butyric acid receptor A (GABAA) genes, particularly the gene encoding the alpha 2 subunit (GABRA2), have been routinely implicated in the etiology of alcohol addiction [14-18]; however see [19, 20] for examples of non-replications. A recent meta-analysis reports that this association with alcohol dependence is significant for rs279858 (odds-ratio 1.18, p=5×10-6), a synonymous and frequently studied SNP [21•]. As the primary inhibitory neurotransmitter, GABAergic mechanisms putatively mediate many of the behavioral effects of alcohol, including sedation, motor impairment and withdrawal (see [22] for review). However, GABAA receptors are heteropentameric and receptors containing the α2 subunit are not directly modulated by ethanol [23]. This led investigators to posit that the well-documented associations between GABRA2 SNPs and alcoholism might be attributed to its comorbidity with other externalizing (e.g., impulsivity) or internalizing (e.g., anxiety) disorders. Consistent with this speculation, studies have noted that the same GABRA2 SNPs linked to alcoholism also correlate with its earliest developmental precursor, conduct problems [24]. In particular, a recent study found that impulsiveness was a nearly complete mediator of the association between GABRA2 SNPs and lifetime alcohol problems [25].
