Causal effects of cholelithiasis on hepatopancreatobiliary diseases: 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 extrahepatic cholangiocarcinoma (eCCA), with consistent directionality across datasets.The association with acute pancreatitis was interpreted as a positive control, whereas the null association with alcohol-induced acute pancreatitis served as a negative control. No causal association was observed for portal vein thrombosis. Sensitivity analyses, including MR-PRESSO and MR Steiger filtering, supported the robustness and directionality of the causal estimates. Reverse MR analyses showed no consistent evidence supporting reverse causality. Multivariable MR indicated that observed effects were not fully explained by BMI-related pathways. CONCLUSION: These findings suggest that cholelithiasis susceptibility may contribute to the broader hepatopancreatobiliary disease network, extending its clinical relevance beyond a localized biliary disorder.