Exploring the causal relationships between cholelithiasis, cholecystitis, cholecystectomy, and gastroesophageal reflux disease: a bidirectional two-sample Mendelian randomization study

Background: Biliary disorders and gastroesophageal reflux disease (GERD) frequently coexist. However, precise linkages between these conditions remain to be clarified. Methods: Univariable Mendelian randomization (MR), Bayesian weighted MR (BWMR) along with multivariable MR approaches were conducted using genetic instruments to evaluate the causality involving biliary disorders and GERD. Furthermore, an investigation was conducted on the potential mediating roles of biliary disorders (or GERD), on the linkage involving BMI and GERD (or biliary disorders). Results: Univariable MR analyses revealed significant causal effects of genetically predicted cholelithiasis [odds ratio (OR)=1.04, P =0.0001], cholecystitis (OR=1.06, P =0.0004), and cholecystectomy (OR=2.56, P =1.05×10 -6 ) on GERD. These findings were replicated in the FinnGen cohort and were also confirmed by BWMR and multivariable MR analyses. Additionally, mediation analyses demonstrated that cholelithiasis and cholecystitis acted as partial mediators, linking BMI causally to GERD. Conversely, GERD exhibited causal effect on cholelithiasis (OR=1.52, P =9.17×10 -30 ) and cholecystitis (OR=1.90, P =3.32×10 -28 ), which remained significant after BWMR and multivariable MR analyses. Mediation analyses further revealed significant mediating effect of GERD on how BMI influenced cholelithiasis/cholecystitis. Conclusion: Our study elucidates the bidirectional causal linkages involving cholelithiasis, cholecystitis, cholecystectomy, and GERD. These results highlight the significance of GERD risk assessment in individuals suffering from biliary diseases and vice versa.