Two genome-wide scans provided evidence for linkage of AD to chromosome 4p (Long et al., 1998; Reich et al., 1998). By fine mapping this region, using family-based association methods, the COGA research group (Edenberg et al., 2004) found that SNPs and their haplotypes throughout the gene encoding the GABAA α2 subunit (GABRA2) were associated with AD. This finding has subsequently been replicated using haplotypic association in different case-control samples (Covault et al., 2004; Enoch et al., 2009; Enoch et al., 2006; Fehr et al., 2006; Lappalainen et al., 2005; Soyka et al., 2008). The significance of these findings is underscored by animal studies, which identify the α-2 subunit as the primary alpha subunit in limbic regions (Fritschy and Mohler, 1995), and a key mediator of the anxiolytic effects of benzodiazepines (Low et al., 2000). However, results of human studies remain contradictory, as demonstrated in a recent report in which no evidence of an association between 3′-GABRA2 polymorphisms and alcoholism was observed in an Italian sample (Onori et al., 2010).
