1. CONTRIBUTION OF COMMON AND RARE VARIANTS TO SCHIZOPHRENIA RISK IN EAST AND SOUTH ASIAN ANCESTRIES

Background Genetic studies of patients with schizophrenia have primarily focused on European ancestries, leaving other populations, including East Asian and South Asian ancestries, underrepresented, potentially increasing health disparities. Methods Here, we report findings from the first large-scale schizophrenia sequencing study examining both common and rare variants in East and South Asian populations (EAS and SAS). We ascertained 96,330 individuals of EAS (cases: 45,711, controls: 50,619) and 20,237 individuals of SAS (cases: 10,377, controls: 9,860) from 10 regions (Mainland China, Hong Kong, Indonesia, Singapore, Japan, Korea, India, Pakistan, Taiwan, and Vietnam). All individuals were genotyped on arrays,or sequenced using Blended Genome Exome (BGE) technology. To enhance genome-wide association studies (GWAS) and rare variant analysis (RVAS), we incorporated European (EUR) cohorts (cases: 53,386, controls: 77,258), achieving a total sample size of 247,211. Results After rigorous QC, imputation and association analyses, we identified 48 independent loci associated with schizophrenia in Asian populations (ASN, EAS+SAS), representing > 5x increase over the largest previous EAS study - including strong signals in the MHC region. In SAS, we found 7 genome-wide significant loci. The SNP-based heritabilities are quite similar across ancestries (20% for EAS, 21% for SAS, and 21% for EUR). We observed high genetic correlations across the three populations: EAS–SAS, 0.86 (0.71–1.00); EAS–EUR, 0.91 (0.86–0.97); and SAS–EUR, 1.08 (0.97–1.20). A multi-ancestry meta-analysis across EUR, EAS, and SAS revealed 461 loci significantly associated with schizophrenia, 131 of which are novel, with SNP-based heritability of 23%. To further investigate the MHC region, we characterized C4 structural variation and its influence on schizophrenia risk in ASN. Comparing haplotype architecture, disease association, and regulatory effects between ASN and EUR revealed substantial ancestry-related divergence. Specifically, ASN exhibit a distinct haplotype architecture; for instance, AL-BS is the most frequent haplotype in ASN (43%) but less common in EUR (31%), while BS is rare in ASN (0.29%) compared to EUR (7%). Despite these differences, odds ratio for major EUR haplotypes (BS, AL-BS, AL-BL, AL-AL) showed no significant difference between ancestries, and C4A and C4B expression in ASN brain samples scaled linearly with their copy number, with slopes indistinguishable from those in EUR.For RVAS, we identified 12 exome-wide significant genes (29 at FDR 5%), including four novel genes (ZMYM2, STAG1, PREP, and SCAF1), and replicated 8 of 10 SCHEMA genes. Schizophrenia RVAS signals were significantly enriched in schizophrenia GWAS loci compared to loci for a non-psychiatric trait (e.g., inflammatory bowel disease; p=0.03). By integrating both common and rare variants, we prioritized genes strongly associated with schizophrenia, such as SCAF1, FYN, and KLC1, which passed the FDR 5% in RVAS and lie near GWAS significant loci. Discussion This study provides, for the first time, insights into the genetic architecture in the SAS population and the integrative contribution of both common and rare variants to schizophrenia risk in three major populations (EAS, SAS, and EUR). These novel findings will enable numerous future investigations and uncover the pathogenesis of schizophrenia, ultimately contributing to the reduction of its disease burden for patients and families across ancestries.