This study, the first GWAS of alcohol-related traits in a Thai population (n=1045 for meta-analysis), adds to the strong literature supporting ALDH2, and most likely functional variant rs671, as protective with respect to alcohol use; and adds novel genetic pleiotropy results. The association was strongest for flushing, next strongest for MAXDRINKS, then AD-CrC – consistent with the accepted mechanism of action, where rs671 inactivates ALDH2, leading to impaired clearing of acetaldehyde, the toxic first metabolic product of ethanol in its primary metabolic pathway. Presumably the aversive effect of the flushing reaction acts as a deterent to ethanol injestion. Acetaldehyde is directly responsible for the flushing reaction (Harada et al., 1981). Rs671, a glutamine to lysine substitution (E487K), results in inactivation of the enzyme subunit (Yoshida et al., 1984). Biochemistry studies – based on ALDH2 activity in liver samples – suggest that the “null” rs671 allele has a nearly dominant effect (Lai et al., 2014, Crabb et al., 1989); the heterozygote retains only about 17% enzyme activity compared to common-allele heterozygotes; minor-allele homozygotes had nearly nil measurable enzyme activity. We did
