Absence of bidirectional causality between primary biliary cholangitis and major depression: A two-sample Mendelian randomization study

Despite a growing body of evidence suggesting an association between primary biliary cholangitis (PBC) and depression, the relationship between the 2 diseases remains to be elucidated due to the limitations of observational studies. Our study aims to clarify the causal relationship between these 2 diseases. We conducted a 2-sample Mendelian randomization (MR) analysis using genetic variant data for PBC and major depression (MD) from the genome-wide association studies catalog. The genome-wide association studies dataset for PBC includes 8021 cases, while that for MD comprises 170,756 cases. We selected instrumental variables (IVs) that met criteria for strong association, independence from confounding factors, and plausible causal pathways. We employed the inverse variance weighting method, supplemented by MR-Egger regression and the weighted median approach, to ensure robustness against potential violations of the IV assumptions. The strength of the association between IVs and the exposure was measured using R2 values and F-statistics, and heterogeneity and horizontal pleiotropy were rigorously assessed to ensure the reliability of the results. The sum R2 values for IV-exposure associations were 10.3733% for PBC and 0.1555% for MD. The F-statistics were all >10. The number of valid IVs exceeded 20. All MR methods indicated no causal relationship between MD and PBC (inverse variance weighting: MD on PBC odds ratio = 1.2168, 95% confidence interval: 0.8356-1.7718, P = .31; PBC on MD odds ratio = 1.0067, 95% confidence interval: 0.9989-1.0145, P = .09). Heterogeneity and horizontal pleiotropy were not detected (P > .05). Our study is the first to investigate the causal relationship between MD and PBC using MR analysis. The results of our study indicate that there is no significant causal relationship between MD and PBC. Despite null genetic causality, depression screening in PBC remains clinically warranted due to symptom burden. Future studies should consider broader populations to address the limitations of our European-only data.