Genes encoding alcohol-metabolism enzymes represented obvious candidates in the study of alcohol use disorder and other alcohol-drinking behaviours and were among the first-studied candidate loci. Alcohol metabolism includes two key steps: alcohol oxidation to acetaldehyde by alcohol dehydrogenases (ADHs), followed by acetaldehyde oxidation to acetate by aldehyde dehydrogenases (ALDHs). Acetaldehyde can cause a wide range of aversive reactions and consequences such as unpleasant or dangerous physical reactions including facial flushing and gastroinstestinal tract cancers50. In ADH1B, the Arg48His amino acid substitution (rs1229984) increases alcohol oxidation activity with respect to the the more common variant in worldwide populations. Analogously, the Glu504Lys amino acid substitution (rs671) in ALDH2 drastically reduces acetaldehyde oxidation activity of the encoded enzyme. Both ADH1BArg48His and ALDH2Glu504Lys cause increases in acetaldehyde levels with respect to a given dose of ethanol and consequently, increases its adverse effects. Due to the high frequency of ADH1BArg48His and ALDH2Glu504Lys variation in some East Asian populations and their pharmacokinetic properties, initial studies explored the association of these alleles with drinking behaviours and alcohol use disorder in Chinese and Japanese individuals51. ADH1BArg48His and ALDH2Glu504Lys
