Transdiagnostic Polygenic Risk Models for Psychopathology and Comorbidity: Cross-Ancestry Analysis in the All of Us Research Program

Psychiatric disorders exhibit substantial genetic overlap, raising questions about the utility of transdiagnostic genetic risk models. Using data from the All of Us Research Program (N=102,091), we evaluated common psychiatric genetic (CPG) factor-based polygenic risk scores (PRSs) compared to standard disorder-specific PRSs. The CPG PRS consistently outperformed disorder-specific scores in predicting individual disorder risk, explaining 1.07 to 24.6 times more phenotypic variance across 11 psychiatric conditions. Meanwhile, many disorder-specific PRSs retained independent but smaller contributions, highlighting the complementary nature of shared and disorder-specific genetic risk. While alternative multi-factor models improved model fit, the CPG PRS provided comparable or superior predictive performance across most disorders, including overall comorbidity burden. Cross-ancestry analyses however revealed notable limitations of European-centric GWAS datasets for other populations due to ancestral differences in genetic architecture. These findings underscore the potential value of transdiagnostic PRSs for psychiatric genetics while highlighting the need for more equitable genetic risk models.