Causal Effects of Inflammatory Cytokines on Bipolar Disorder: A Bidirectional Two‐Sample Mendelian Randomization Study

Introduction Inflammatory cytokine disturbance is a prominent outcome of immune dysregulation, extensively documented in bipolar disorder (BD). However, observational studies have exhibited inconsistent findings, and the causal relationships between inflammatory factors and BD remain unclear. Hence, this study aimed to uncover the causality between circulating inflammatory cytokines and BD. Methods In the bidirectional Mendelian randomization (MR) analysis, two genetic instruments derived from a publicly available genomic dataset were utilized. Genetic variant data for 41 inflammatory cytokines were obtained from a meta‐analysis of genome‐wide association studies involving 8293 Finnish individuals. BD data included 41,917 cases and 371,549 controls from the Psychiatric Genomics Consortium Database. To estimate causal connections between inflammation cytokines and BD, we performed five methods: inverse variance weighting (IVW), MR‐Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses were conducted to evaluate robustness, including tests for heterogeneity, pleiotropy, and leave‐one‐out validation. Results In the IVW approach, we identified significant associations between genetic liability to elevated levels of interleukin‐17 (IL‐17), macrophage inflammatory protein‐1α (MIP‐1α), and monocyte chemotactic protein 3 (MCP‐3) with increased risk of developing BD (odds ratio [OR] = 1.119, 95% confidence interval [CI] = 1.021–1.226, p = 0.016; OR = 1.084, 95% CI = 1.002–1.174, p = 0.044; OR = 1.060, 95% CI = 1.001–1.122, p = 0.046, respectively). Across the various MR methods employed, the directions of causal inferences remained consistent. However, reverse MR analysis revealed no significant evidence for causal effects of genetic predisposition to BD on inflammatory cytokines. Conclusion Our findings provide robust genetic evidence supporting causal effects of elevated circulating inflammatory cytokines on BD, conferring a high susceptibility to BD. Our study emphasizes that interventions aimed at reducing peripheral inflammatory cytokine levels should be prioritized in BD management.