Shared Genetic Architecture of Psychosis, Mood, and Cognition in East Asian Ancestry

Genomic insights into psychiatric disorders remain heavily skewed toward European populations. In European-ancestry studies, educational attainment is typically negatively genetically correlated with major depression but paradoxically positively correlated with schizophrenia, raising the question of whether these relationships generalize across ancestries. We investigated whether this cross-trait architecture extends to East Asian ancestry (EAS). Using EAS GWAS summary statistics for major depressive disorder (MDD), schizophrenia (SZ), and educational attainment (EDU), we applied multi-trait (MTAG) and pleiotropy-informed (PLEIO) analyses to characterize shared genetic architecture across these traits. Across MTAG and PLEIO analyses, we identified 32 unique genome-wide significant loci (p < 5 x 10-8), including seven novel loci revealed in depression analysis that overlapped schizophrenia-associated signals, consistent with shared cross-trait architecture. Results reinforce a convergent risk architecture for affective and psychotic disorders in this population. Fine-mapping analyses prioritized variants mapping to candidate genes, including serine/threonine kinase VRK2, nominating targets for future follow-up. Cross-trait analyses supported a positive genetic relationship between EDU and MDD (rg = 0.308, p = 9.63 x 10-17) in East Asian data, contrasting to the negative correlation typically observed in European ancestry. These findings suggest that the genetic relationship between educational attainment and psychiatric risk may not be fully transferable across ancestries. In an independent cohort of individuals at ultra-high risk for psychosis, MTAG-derived polygenic risk scores improved case-control discrimination relative to single-trait GWAS-based scores. These results underscore the importance of ancestry-specific genomic frameworks for interpreting cross-trait psychiatric architecture and improving polygenic prediction.