The GABA system gene by far most frequently implicated in alcohol-related behaviors and other substance-related and externalizing behaviors is the GABAA receptor α2 subunit gene GABRA2. The SNP rs279858, though lying in exon 5 of the gene, is a synonymous substitution (Covault et al., 2004). It has been associated, either individually or as a member of multi-SNP haplotypes, with alcohol dependence and other alcohol related phenotypes, such as alcohol sensitivity, more often than any other marker in GABRA2 (Cui et al., 2012). Although the genome-wide array upon which markers were genotyped for our study did not include rs279858, it did include markers in the same region of the gene (rs1808851, rs279856), which were in perfect LD with rs279858 in a HapMap reference panel of European descent (CEU) (Johnson et al., 2008) —but neither of which were associated at even a nominal level with either the drinking index or alcohol abuse and dependence symptom count. Synonymous SNPs can affect protein functioning and expression via a number of different mechanisms (Hunt et al., 2009), so genotyping the exact SNP associated with alcohol-related phenotypes in previous studies may be critical.
