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ALDH2 is a key enzyme in alcohol metabolism that protects cells from acetaldehyde toxicity. Using iHS, iSAFE and  F   ST   statistics, we identified regulatory acting variants affecting  ALDH2  gene expression under positive selection in populations of European ancestry. Several SNPs (rs3184504, rs4766578, rs10774625, rs597808, rs653178, rs847892, rs2013002) that function as eQTLs for  ALDH2  in various tissues showed evidence of strong positive selection. Very large pairwise  F   ST   values indicated high genetic differentiation at these loci between populations of European ancestry and populations of other global ancestries. Estimating the timing of positive selection on the beneficial alleles suggests that these variants were recently adapted approximately 3000–3700 years ago. The derived beneficial alleles are in complete linkage disequilibrium with the derived  ALDH2  promoter variant rs886205, which is associated with higher transcriptional activity. The SNPs rs4766578 and rs847892 are located in binding sequences for the transcription factor  HNF4A,  which is an important regulatory element of  ALDH2  gene expression. In contrast to the missense variant  ALDH2  rs671 ( ALDH2*2 ), which is common only in East Asian populations and is associated with greatly reduced enzyme activity and alcohol intolerance, the beneficial alleles of the regulatory variants identified in this study are associated with increased expression of  ALDH2 . This suggests adaptation of Europeans to higher alcohol consumption.

Positive selection acts on regulatory genetic variants in populations of European ancestry that affect ALDH2 gene expression