Causal effects of cholelithiasis on acute pancreatitis and hepatic bile duct cancer: a multi-cohort Mendelian randomization study

Background : Cholelithiasis is commonly associated with multiple hepatopancreatobiliary diseases, yet whether these relationships reflect causal mechanisms or shared risk factors remains unclear. Methods : We performed a phenome-oriented two-sample Mendelian randomization (MR) analysis to evaluate the causal impact of genetic liability to cholelithiasis across hepatopancreatobiliary outcomes. Independent genome-wide significant variants were selected as instrumental variables. Primary analyses used inverse variance weighting, complemented by sensitivity analyses, reverse MR, and multivariable MR adjusting for body mass index (BMI). Results : Genetic predisposition to cholelithiasis was associated with increased risk of acute pancreatitis and hepatic bile duct cancer, with consistent directionality across datasets. No causal association was observed for portal vein thrombosis. Sensitivity analyses showed no evidence of directional pleiotropy, and reverse MR analyses did not support bidirectional causality. Multivariable MR indicated that observed effects were not fully explained by BMI-related pathways. Conclusion : These findings suggest that cholelithiasis susceptibility may function as an upstream determinant within the hepatopancreatobiliary disease network, extending its clinical relevance beyond a localized biliary disorder. These findings highlight the potential clinical value of gallstone susceptibility in risk stratification and prevention of hepatopancreatobiliary diseases.