Since both highly-active ADHs and highly-inactive ALDHs have the potential to cause increased circulating acetaldehyde levels, several authors hypothesized their possible involvement in population differences in alcohol sensitivity [Goedde and others 1979; Stamatoyannopoulos and others 1975]. These variant ADH and ALDH isoforms are encoded by gene alleles with nonsynonymous substitutions in the encoded proteins (those in ADH1B are discussed above) and in 1991, in one of the first studies in psychiatric genetics to use a molecular approach, Thomasson and colleagues demonstrated that ADH1B*2 (Arg48His, rs1229984) and ALDH2*2 (Glu504Lys, rs671) are associated with reduced risk of alcoholism in an Asian sample [Thomasson and others 1991]. Notwithstanding the small size of the sample used in this study, the findings have been confirmed many times since. Subsequently, numerous gene-candidate studies showed that, although ADH1B rs1229984 minor allele frequency (MAF) is lower in non-Asian populations than that observed in Asians, it is protective with respect to alcohol drinking behaviors also in other ancestries [Li and others 2011a; Luo and others 2006]. Conversely, ALDH2 rs671 is very rare in non-Asian populations (MAF < 1% in accordance with 1,000 Genomes Project Phase 3 data; [1000 Genomes Project Consortium and others 2015]) and no informative analysis can
