Genome-wide Association Study Reveals 27 Novel Loci Associated with Gallstone Disease

Abstract

Introduction: Gallstones have a prevalence of 20-40% in European populations and cause significant morbidity. Associated complications include pancreatitis and gallbladder cancer. Gallstones are polygenic but it is likely many determinants are undiscovered. The aim of this study was to identify novel genetic variants that represent new targets for gallstone research using a genome-wide association study (GWAS). Method: GWAS of 16,356,211 single nucleotide polymorphisms (SNPs) for 28,627 cases and 348,373 controls of European ancestry in the UK Biobank was undertaken. An age-, sex- and population-structure-adjusted logistic regression was performed (significance: P<5*10-8). Functional annotation and linkage disequilibrium clumping were performed to reveal distinct loci. Lead SNPs were investigated by linear regression for association with serum lipids and liver enzymes. Results: 55 lithogenic loci were identified of which 27 are novel. Functional annotation revealed genes involved in cholesterol, glucose, bile acid and bilirubin metabolism with corresponding changes in biomarkers caused by lithogenic alleles. Several novel variants did not influence any biomarkers. Lithogenic variants within genes controlling paracellular transport may alter biliary composition (PCDHB4, NUP153, CLDN7), promoting lithogenic bile. Variants within genes which may influence gallbladder motility (ANO1, TMEM147) and cholangiocyte ciliogenesis (TBC1D32, ADAMTS20, DYNC2LI1, HNF1B) may promote gallstone formation by altering biliary flow. Conclusions: We identified 27 novel lithogenic variants. Several novel variants appear to influence gallstone formation through pathways not involving cholesterol, glucose or bilirubin metabolism. The novel loci may influence biliary composition, bile flow and gallbladder motility providing new targets for research into aetiology and prevention of gallstones and related complications.