A genome-wide cross-trait analysis characterises the shared genetic architecture between rheumatoid arthritis and psychiatric disorders.
OBJECTIVES Patients with rheumatoid arthritis (RA) have a 2- to 3-fold elevated risk of psychiatric disorders, suggesting an underlying genetic link between these phenotypes. However, the shared genetic architectures and pathological mechanisms driving RA-psychiatric disorder comorbidity remain to be fully elucidated. Herein, we performed cross-trait analysis to investigate the shared genetic architecture between RA and psychiatric disorders. METHODS Leveraging European-ancestry genome-wide association studies (GWASs) datasets of RA (N = 1,026,690) and ten major psychiatric disorders (N = 14,307 to 1,222,882), we performed cross-trait pleiotropic analysis to identify the shared pleiotropic loci and genes between RA and psychiatric disorders, followed by functional annotation and Mendelian randomization analysis to explore the pathological mechanisms underlying RA-psychiatric disorder comorbidity. RESULTS Our analysis revealed significant positive genetic correlations between RA and seven psychiatric disorders, such as major depressive disorder. From these correlations, we identified 61 pleiotropic loci jointly influencing RA and psychiatric disorder risk, along with 208 pleiotropic genes predominantly involved in immune and inflammatory response biological processes. Druggable target exploration identified 21 drug-gene interactions involving pleiotropic genes, with two genes (RHOA and TRAF3) classified as clinically actionable category, representing potential therapeutic target for both RA and psychiatric disorders. Mendelian randomization further demonstrated a bidirectional causal relationship between RA and SCZ, while supporting the causal roles of ADHD, MDD, and PTSD in increasing RA risk. CONCLUSIONS Our findings elucidate the shared genetic architecture between RA and psychiatric disorders, providing novel insights into the pathological mechanisms underlying their comorbidity and laying groundwork for improved comorbidity management.