Trans-ancestry genome-wide association meta-analysis of gallstone disease

Gallstone disease is a highly prevalent and costly gastrointestinal disease. Yet, genetic variation in gallstone susceptibility and its implication in metabolic pathways remain to be explored. We report a trans-ancestry genome-wide association meta-analysis of gallstone disease including 100,856 cases and 1,596,602 controls in the UK Biobank, FinnGen, Biobank Japan, and Million Veteran Program. We identified 116 (59 novel) risk loci across 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. Colocalization of risk loci with 44 traits and with expression quantitative trait loci from eight tissues yielded 321 and 110 significant colocalizations, respectively. These findings broaden our understanding of the genetic architecture of gallstone disease.