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

<p><span>An East Asian-specific variant on <em>aldehyde</em> <em>dehydrogenase</em> <em>2</em> (<em>ALDH2</em> rs671, G&gt;A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study (GWAS) meta-analysis in up to 175,672 Japanese individuals to uncover additional loci associated with alcohol consumption in an rs671-dependent manner. Three loci (<em>GCKR</em>, <em>KLB</em>, and <em>ADH1B</em>)</span> <span>satisfied the genome-wide significance threshold in wild-type homozygotes (GG), whereas six loci (<em>GCKR</em>, <em>ADH1B</em>, <em>ALDH1B1</em>, <em>ALDH1A1</em>, <em>ALDH2</em>, and <em>GOT2</em>) did so in heterozygotes (GA). Of these, five loci showed genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Subsequent polygenic risk scoring depicted interactions highlighted by stratified GWAS. Further, most discovered loci showed significant effects on risk of esophageal cancer, a representative alcohol-related disease, and multiple other phenotypes. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.</span></p>