Koyanagi YN, Nakatochi M, Namba S, Oze I, Charvat H, Narita A, Kawaguchi T, Ikezaki H, Hishida A, Hara M, Takezaki T, Koyama T, Nakamura Y, Suzuki S, Katsuura-Kamano S, Kuriki K, Nakamura Y, Takeuchi K, Hozawa A, Kinoshita K, Sutoh Y, Tanno K, Shimizu A, Ito H, Kasugai Y, Kawakatsu Y, Taniyama Y, Tajika M, Shimizu Y, Suzuki E, Hosono Y, Imoto I, Tabara Y, Takahashi M, Setoh K, Matsuda K, Nakano S, Goto A, Katagiri R, Yamaji T, Sawada N, Tsugane S, Wakai K, Yamamoto M, Sasaki M, Matsuda F, Okada Y, Iwasaki M, Brennan P, and Matsuo K
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.