Early COGA studies focused on non‐synonymous variants in single genes with high risk for AUD. A major focus of the AUD candidate gene literature has been on genes encoding alcohol‐metabolizing enzymes, such as alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). 40 The associations between AUD and SNPs in ADH1B and ALDH2 represent some of the largest effect sizes in psychiatry. Studies of a non‐synonymous variant in ADH1B (rs1229984), resulting in the replacement of Arginine (R48) with Histidine (H48), show that individuals with the minor allele demonstrate reduced risk for AUD. 40 , 41 , 42 It was hypothesized that dramatic change in enzyme activity (H48 oxidizes ethanol approximately 70‐ to 80‐fold faster than R48) leads to transient elevation of acetaldehyde and development of aversive behavior associated with alcohol due to experience of severe flushing. Variations in ALDH2 (rs671; E504K), the mitochondrial acetaldehyde dehydrogenase, that greatly reduce its activity and thereby increase acetaldehyde levels, were also associated with AUD. 40 , 43 Although ADH1B and ALDH2 have by far the strongest known effects on risk for AUD, other candidate genes and heritable traits are known to predict AUD liability.
