Decomposing population differences in type 2 diabetes through a high-resolution GWAS of ~600,000 individuals with East Asian ancestry

Abstract

Type 2 diabetes (T2D) is a highly heterogeneous metabolic trait, with a higher prevalence in East Asians. Despite extensive genetic studies focusing mainly on Europeans, how genetic risk for T2D is distributed across biological pathways in East Asians in comparison with Europeans remains incompletely understood. Here, we show results from what is, to our knowledge, the largest genome-wide association study in East Asians, including 596,778 individuals, with a direct comparison to a European study of comparable sample size. We identified 196 loci, including three previously unreported loci. Subsequent multi-ancestry fine-mapping resolved 521 independent causal signals with high precision, revealing that 74% are shared while the remainder are strictly ancestry-specific. Beyond this shared architecture, we observed population differences in regulatory and pathway-level contributions, particularly involving pancreatic regulation and lipid- or adipose-related pathways. Furthermore, constructing a polygenic risk score using the cross-ancestry meta-analysis yielded the most robust predictive performance (AUC = 0.788). These findings clarify how T2D genetic risk is organized across populations, demonstrating that while multi-ancestry integration maximizes clinical predictive power, well-powered single-ancestry studies remain indispensable for uncovering population-specific biological mechanisms. A GWAS of ~600,000 East Asian individuals shows that the genetic architecture of type 2 diabetes is largely shared with European ancestry individuals, yet population differences concentrate in specific pathways, underscoring the value of well-powered single-ancestry studies