Biological Psychiatry Global Open Science · Published 2026-03-30 · DOI 10.1016/j.bpsgos.2026.100727
Background: Schizophrenia imposes a substantial global health burden, with marked geographic variation in incidence, prevalence, and disability-adjusted life years (DALYs). Although genome-wide association studies (GWASs) have identified numerous individual-level risk variants, it remains unclear whether cross-population differences in allele frequencies are associated with variation in population-level disease burden. Methods: We integrated allele frequencies from the 1000 Genomes Project with age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR), and age-standardized DALY rate (ASDR) across 20 countries (1990–2021) using the Global Burden of Disease 2021 data. Associations between allele frequencies and burden metrics were evaluated using linear mixed-effects models. Independent signals were defined through linkage disequilibrium–based clumping and annotated via multi-omic gene prioritization. Polygenic risk score (PRS) analyses were conducted in the UK Biobank for validation. Results: We identified 20, 20, and 14 independent single nucleotide polymorphisms (SNPs) significantly associated with ASIR, ASPR, and ASDR, respectively. Two loci overlapped with Psychiatric Genomics Consortium GWAS findings, including variants within ADGRV1 and upstream of STAG1. These loci collectively explained a meaningful proportion of cross-country variation (partial R2 = 0.13–0.22). Implicated genes (e.g., LRRC4C, GPC5, PVALB) are involved in neurodevelopmental and synaptic processes. In UK Biobank analyses, schizophrenia cases exhibited higher PRSs derived from ASIR- and ASPR-associated SNPs (p = .0024 and .0095). Conclusions: These findings suggest that population-level allele frequency variation is associated with global differences in schizophrenia burden and accounts for a meaningful proportion of cross-population variation. This transferable population-genomic epidemiological framework may inform future research on complex diseases and mental health disparities.
Abstract from DOAJ. Public domain (CC0 1.0).
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