AD is moderately heritable (49% by a recent meta-analysis)5 and numerous genome-wide association studies (GWAS) have aimed to identify loci contributing to this genetic variance (see6 for a review). According to one study, common SNPs are responsible for as much as 30% of the variance in AD7, but few have been identified to date. Variants in the genes responsible for alcohol metabolism, especially ADH1B and ALDH2, have been strongly implicated8–13. The association between AD (and related drinking phenotypes) and rs1229984, a missense SNP (Arg48His) in ADH1B that affects the conversion of alcohol to acetaldehyde, represents one of the largest common-variant effect sizes observed in psychiatry, with the His48 allele accelerating ethanol metabolism and affording approximately 3-fold reduction in likelihood of AD across numerous studies8,10. Another functional polymorphism, rs671 in ALDH2 (Glu504Lys), strongly affects alcohol metabolism by blocking conversion of acetaldehyde to acetate and has an even stronger effect on risk for AD, but is rare except in some Asian populations8,12,13 ADH1B and ALDH2 polymorphisms, however, only explain a small proportion of the heritable variation in AD in populations of European or African ancestry.
