Genetic Liability to Psychiatric Disorder and Risk of Musculoskeletal Diseases: A Bidirectional Mendelian Randomization Study

Abstract

Background: Psychiatric disorders, particularly major depressive disorder (MDD), are increasingly recognized as systemic diseasesthat may predispose individualsto a range of physical comorbidities. Epidemiological studies have reported associations between depression and musculoskeletal diseases; however, causal inferences remain limited due to confounding factors and reverse causation. This study aims to investigate the bidirectional causal relationships between common psychiatric disorders and musculoskeletal outcomes using a Mendelian randomization (MR) framework.

Methods: A bidirectional two-sample MR analysis was conducted using summary statistics from a large-scale genome-wide association study (GWAS) in European ancestry populations. Genetic instruments for seven psychiatric disorders were obtained from the Psychiatric Genomics Consortium, while musculoskeletal outcomes were sourced from the IEU Open GWAS and UK Biobank. Causal effects were primarily estimated using an inverse variance weighted model, with sensitivity analyses conducted using the weighted median (WM) and MR-Egger methods. Established diagnostic methods were employed to assess horizontal pleiotropy, heterogeneity, and robustness, and false discovery rate (FDR) corrections were applied to account for multiple testing.

Results: The genetic liability to MDD showed the most consistent evidence of association with osteoarthritis (OA) and osteomyelitis (OM). The association with OA appeared to be the most stable overall, while the findings regarding OM should be interpreted more cautiously due to the relatively limited number of available instrumental variables. Nominal associations were also observed for fracture and osteoporosis (OP) in relation to MDD, as well as between autism spectrum disorder (ASD) and fracture risk and between anorexia nervosa (AN) and fracture risk; however, these findings were either modest in magnitude or did not remain significant after multiple-testing correction, and thusshould be considered exploratory results. There was no strong evidence supporting a reverse causal effect of musculoskeletal diseases on psychiatric disorders.

Conclusions: This MR study suggests that genetic liability to MDD may be associated with susceptibility to specific musculoskeletal diseases, particularly OA, and more cautiously, OM. These findings should be interpreted with caution, especially for associations based on limited instrumental support or modest effect sizes, and require replication in different populations.