The GWAS-identified variants include missense functional SNPs that alter the alcohol metabolism pathway converting alcohol to acetaldehyde via ADH enzymes and then to acetate via ALDH enzymes. For example, the ADH1B SNP allele rs1229984-T is a missense variant that alters enzymatic activity resulting in up to 100-fold higher rate of alcohol to toxic acetaldehyde metabolism, causing the alcohol flush reaction, and reducing susceptibility to developing alcohol drinking problems [90]. Moreover, the rs671-A allele in ALDH2, another missense variant, alters the latter step of the alcohol metabolism pathway by greatly reducing ALDH2 activity and rendering high acetaldehyde concentrations upon alcohol exposure [85]. Both the ADH1B rs1229984-T and ALDH2 rs671-A alleles occur frequently in East Asian populations but infrequently in other world populations, and their highly significant associations with reduced susceptibility to drinking alcohol and developing an addiction were studied as candidate SNPs based on their functional consequences on enzymatic activity before they were highlighted via agnostic GWAS [85, 91]. Associations of these SNPs or their proxies on alcohol-related disease outcomes include coronary heart disease [85], various cancers [92, 93], renal function
