Cross-ancestry and cross-disorder transferability of polygenic risk scores for obsessive-compulsive disorder

Most genome-wide association studies (GWASs) of obsessive-compulsive disorder (OCD) have been conducted in European populations, limiting the understanding of OCD genetics across populations. Here, we investigated the cross-ancestry and cross-disorder transferability of European-derived polygenic risk scores (PRSs) for OCD in the first East Asian OCD cohort. We performed a GWAS in 532 Korean OCD cases and 4376 controls, followed by PRS analyses using European GWASs for OCD and 10 psychiatric disorders. The European-derived OCD PRS was significantly associated with Korean OCD status (best-fit R² = 1.17%). In multivariable models, PRSs for OCD (odds ratio [OR] = 1.28, 95% confidence interval [CI] = 1.13-1.45), schizophrenia (SCZ; OR = 1.17, 95% CI = 1.03-1.32), and anorexia nervosa (AN; OR = 1.17, 95% CI = 1.03-1.32) were independently associated with OCD. A stepwise multi-PRS model including PRSs for OCD, AN, SCZ, post-traumatic stress disorder, anxiety disorder, attention deficit hyperactivity disorder, and bipolar disorder (BD) yielded the highest predictive performance (incremental R² = 2.99%). Where available, we evaluated PRSs derived from East Asian, European, and combined populations. For BD and SCZ, PRSs derived from cross-ancestry meta-analysis GWASs showed the greatest predictive performance for OCD, outperforming single-ancestry PRSs (incremental R² = 2.84 and 1.28%, respectively). Our findings demonstrate cross-ancestry transferability of OCD polygenic risk and highlight substantial genetic overlap between OCD and other psychiatric disorders, particularly SCZ and AN. Together, they underscore the importance of including diverse ancestral populations in psychiatric genetics and suggest that transdiagnostic polygenic frameworks may provide deeper insight into the biological basis of OCD.