Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS, and impact on esophageal cancer risk in Japanese people

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671,
G>A) is the major genetic determinant of alcohol consumption. We
performed an rs671 genotype-stratified genome-wide association study
meta-analysis of alcohol consumption in 175,672 Japanese individuals to
explore gene-gene interactions with rs671 behind drinking behavior. The
analysis identified three genome-wide significant loci (GCKR, KLB, and
ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1,
ALDH2, and GOT2) in heterozygotes, with five showing genome-wide
significant interaction with rs671. Genetic correlation analyses revealed
ancestry-specific genetic architecture in heterozygotes. Of the discovered
loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact
with rs671 in the risk of esophageal cancer, a representative
alcohol-related disease. Our results identify the genotype-specific
genetic architecture of alcohol consumption and reveal its potential
impact on alcohol-related disease risk.