Abstract
Gallstone disease is a highly prevalent and costly gastrointestinal disease. Yet, genetic variation in susceptibility to gallstone disease and its implication in metabolic regulatory pathways remain to be explored. We report a trans-ancestry genome-wide association meta-analysis of gallstone disease including 88,063 cases and 1,490,087 controls in the UK Biobank, FinnGen, Biobank Japan, and Million Veteran Program. We identified 91 (37 novel) risk loci across the meta-analysis and found replication in statistically compelling signals in the All of Us Research Program. A polygenic risk score constructed from trans-ancestry lead variants was positively associated with liver chemistry and alpha-1-antitrypsin deficiency and negatively associated with total cholesterol and low-density lipoprotein levels among trans-ancestry and European ancestry groups in the Penn Medicine BioBank. Cross-trait colocalization analysis between risk loci and 44 liver, metabolic, renal, and inflammatory traits yielded 350 significant colocalizations as well as 97 significant colocalizations and 65 prioritized genes from expression quantitative trait loci from eight tissues. These findings broaden our understanding of the genetic architecture of gallstone disease.