Abstract Purpose Many observational studies have revealed intriguing connections between multisite chronic pain (MCP) and psychiatric disorders. Yet, the critical question of causality remains elusive. Our aim was to systematically evaluate the causal relationships between MCP and 11 psychiatric disorder subtypes while identifying potential mediators. Methods We adopted a three-stage two-sample bi-directional Mendelian randomization (MR) analysis to ensure the robustness and reliability of our findings. MCP summary data was sourced from a genome-wide association study with 387,649 individuals in the UK Biobank. The discovery stage used summary statistics mainly from the Psychiatric Genomics Consortium, while validation involved MR analysis with data from the FinnGen consortium. Meta-analysis was conducted to pool MR estimates from the discovery and validation stages. Results Positive causal relationships were found between MCP and 7 psychiatric disorder subtypes, including depression, panic disorder, anxiety disorders, insomnia, attention deficit hyperactivity disorder, post-traumatic stress disorder, and bipolar disorder, with combined odds ratios ranging from 1.361 ( P < 0.00001) to 3.322 ( P < 0.0045). Reverse MR revealed bidirectional causal associations between depression and MCP, along with anxiety disorders and MCP ( P < 0.05). Additionally, causal links were identified between MCP and smoking initiation, physical activity, body mass index, and changes in human blood cells. Multivariable MR analysis indicated these factors may mediate the relationship between MCP and psychiatric disorders. Conclusion Our findings provide novel insights into the involvement of MCP in psychiatric disorders, highlighting potential modifiable risk factors to reduce their incidence.
Lin et al. (2025) studied this question.