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

Abstract

An East Asian-specific variant on <i>aldehyde dehydrogenase 2</i> (<i>ALDH2</i> 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 (<i>GCKR</i>, <i>KLB</i>, and <i>ADH1B</i>) in wild-type homozygotes and six (<i>GCKR</i>, <i>ADH1B</i>, <i>ALDH1B1</i>, <i>ALDH1A1</i>, <i>ALDH2</i>, and <i>GOT2</i>) 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 (<i>GCKR</i>, <i>ADH1B</i>, <i>ALDH1A1</i>, and <i>ALDH2</i>) 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.