Genome-wide Analysis Identifies Novel Gallstone-susceptibility Loci Including Genes Regulating Gastrointestinal Motility

Abstract Objective Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely many genetic determinants are undiscovered. The aim of this study was to identify novel genetic variants that represent new targets for gallstone research and treatment. Design We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank and a GWA meta-analysis (43,639 cases and 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of implicated genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Results Seventy-five risk loci were identified (P<5*10 −8 ) of which forty-six were novel. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism and gastrointestinal motility. ANO1 and TMEM147 , both in novel loci, are strongly expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression suggesting the protein protects against gallstone formation. Individuals in the highest decile of the PRS demonstrated a 6-fold increased risk of gallstones compared to the lowest risk category. The PRS was strongly associated with increased body mass index, serum liver enzyme and C-reactive protein concentrations and decreased lipoprotein cholesterol concentrations. Conclusion This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. For the first time, we implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones. Summary Box What is already known on this subject? Genome-wide association studies (GWAS) have identified 29 genetic variants within independent loci which increase the risk of gallstone disease. Most of these variants lie within or near to genes that regulate lipid or bile acid metabolism. Gallstones are known to have a significant genetic component with 25-50% of gallstone disease due to genetic risk factors. Much of this risk is not accounted for by the known gallstone-susceptibility loci. What are the new findings? We performed a GWAS in the UK Biobank (28,627 gallstone cases, 348,373 controls) and a GWA meta-analysis (43,639 cases and 506,798 controls) with the FinnGen cohort. We identified a total of 75 gallstone-susceptibility loci with 46 of these being new and the remaining 29 being those already identified. We annotated the variants based on their position within or near to genes and assessed pathway enrichment through gene-set analysis. We identify two novel gallstone-susceptibility loci in which the lead variants lie within genes governing gastrointestinal motility which highly expressed in gallbladder ( ANO1 and TMEM147 ). We demonstrate further loci involved in primary cilia function. We report significant association of a polygenic risk score with gallstones using independent subsets of the study population. How might it impact on clinical practice in the foreseeable future? The genes and pathways identified represent novel targets for development of medication targeting primary or secondary prevention of gallstones. This may be of particular benefit to those unable to undergo cholecystectomy. The individual variants or polygenic risk score identified in this GWAS could form the basis for identification of individuals with high risk of gallstones to support screening or treatment of gallstone disease. This screening may be of particular benefit in populations with elevated risk of gallstones such as haemolytic disease or bariatric surgery.