Abdominal obesity mediates the causal relationship between depression and the risk of gallstone disease: retrospective cohort study and Mendelian randomization analyses

Objective: Our study aimed to explore the causal effect of depression on the risk of gallstone disease, and the mediation effects of metabolic traits. Methods: A retrospective cohort study on Chinese elderly from the Dongfeng-Tongji cohort (including 18,141 individuals) was conducted to estimate the adverse effect of probable depression on the risk of gallstone disease. Two-sample Mendelian randomization was performed in European and East-Asian ancestries, to verify the causal relationship between major depression and gallstone disease. We further applied two-step Mendelian randomization to explore the mediation effects of metabolic traits. Results: In the cohort study, probable depression was associated with an increased risk of gallstone disease within 5 years, with RR (95% CI) of 1.33 (1.12, 1.58) in multivariable regression, and 1.34 (1.11, 1.61) following propensity score weighting. Bidirectional Mendelian randomization in European ancestry revealed a positive causal effect (OR: 1.21; 95% CI: 1.07 to 1.37) of genetically predicted major depression liability on gallstone disease, based on the inverse variance weighted method. Little evidence was presented from other complementary approaches, and the analysis in East-Asian ancestry (IVW estimated OR: 1.03; 95% CI: 0.92 to 1.15). The indirect effect via waist circumference and HDL-C were 1.06 (95% CI: 1.02 to 1.10) and 1.01 (95% CI: 1.00 to 1.01) respectively, which mediated 25.8% and 3.78% of the causal relationship. Conclusions: Our study suggested a higher risk of gallstone disease in the population with probable depression, while the two-sample Mendelian randomization provided weak evidence for the causal relationship, which was moderately mediated by abdominal obesity.