AD is moderately heritable, with heritability in most studies estimated to be 0.50–0.60.4 Pre-GWAS, risk-influencing alleles were identified for AD via genetic linkage analysis, candidate gene association analysis and the productive use of endophenotypes. The best known and replicated risk alleles map to alcohol-metabolizing enzyme genes, especially ADH1B,5 ADH1C6 and ADH4,7 on chromosome 4 and the chromosome 12 locus ALDH2.8 In some Asian populations, protective alleles at these loci are common, resulting in either delayed degradation or increased production of the toxic alcohol metabolite acetaldehyde.
