The only consistent findings from classical GWAS of AD are those implicating the alcohol metabolizing enzyme genes, which have shown association in GWAS for AD and a proposed intermediate phenotype for AD, alcohol consumption (Baik et al., 2011; Frank et al., 2012; Gelernter et al., 2014a; Kapoor et al., 2013; Park et al., 2013; Quillen et al., 2014; Schumann et al., 2011; Takeuchi et al., 2011), replicating findings from candidate gene studies of AD. The lack of consistent findings overall may reflect low power to detect variants of small effect and genetic and phenotypic heterogeneity among studies. Thus, the SNPs in the genes encoding metabolizing enzymes are among the common variants with the largest effects on AD risk. Interestingly, associations with other candidate genes for AD such as DRD2, OPRM1, and COMT have not been replicated in GWAS (Olfson and Bierut, 2012), suggesting that their presumed effect sizes have been greatly overestimated in candidate gene studies, where small sample sizes have been used to detect significant effects (P<0.05), or they are false positives.
