biostudies-literatureGuo BU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Novo Nordisk Fonden (Novo Nordisk Foundation)U.S. Department of Health & Human Services | National Institutes of Health (NIH)Qatar National Research Fund (QNRF)8632https://www.ebi.ac.uk/biostudies/studies/S-EPMC12488948biostudies-literatureUnknown16(1)Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traitsNature communicationsPolygenic risk score for type 2 diabetes shows context-dependent effects across populations.PMC12488948P50CA097186R01HD30880R01HL142302UM1DK078616R01HL163262R00CA246063NNF20OC0059313U01CA261339P30CA015704PPM2-0226-170020R01HL151152R01HL174378NNF18CC0034900NPRP11S-0114-180299R01DK123019R01HL156991R01DK122503R03CA287235R01HL143885U54HG013243R01DK139598Larsen CCrawford Jbiobank at the Colorado Center for Personalized Medicine (CCPM)Lacy RWhitbourne SBPozdeyev NHighland HMCulver EDarst BFStewart AMKu LWiley LLee NRChang KMClarke SLShuey MMGuo BBroadaway KABuyske SCasteel EMPatki ADManson JEMoser JDuVall SLNadrash ATodd EBSmit RAJLankester JBrewer JVGignoux CEaston CBYousri NAHauser EKranzler HChurby LMarchand LLVanderwerff BTrinkley KELin MShayan SAStanislawski MKim DMcDaniel NLMeigs JBGordon-Larsen PStæger FFGraff MKudron ELLoos RJFGeorge HAquilante CLSutton KJDeen JEKilbourne ACox NJVoora DGilliland EKLowery JTMarceau DBjerregaard PBrutus-Lestin JZhou XWilkens LRBoehnke MArbogast KKooperberg CHearst EFranklin AWMohlke KLBrunetti TMMatheny MRotter JIPattee JJulian CGCoughlin CRArehart CHRich SSTeague CRadwan ARaghavan SSwartz CTStephens BIyer KRHaessler JRafaels NDavis LAlbrechtsen ASun QPeters UWang YJorgensen MEWang ZOslin DMaldonado BLMoltke IShalowitz ELTsao PSRaffield LMEdelmann MNLee YMJohnson RKAnderson HDTanaka ABrophy MTYang CShortt JTaylor MRGManichaikul AAssimes TLMartin JLSherif HVargas LBFisher MJGreene CSFrye TCLesny JABurke EEHung AHawkes BMayer DLiu SBrooks IMMuralidhar SPyarajan SMonte AStalbow LKao DHendricks AECho KKonigsberg ISelva LEGuarischi-Sousa RHaiman CAYin XRasouli NStraub PSGates BLVA Million Veteran Program (MVP)Stram DOCarlson CSCrooks KHilliard ATHansen TRinger RLange EMWiley LKCole JBCai YTao RIrvin RMGaziano JMMoore ENorth KEfalsePolygenic risk score for type 2 diabetes shows context-dependent effects across populations.Polygenic risk scores hold prognostic value for identifying individuals at higher risk of type 2 diabetes. However, further characterization is needed to understand the generalizability of type 2 diabetes polygenic risk scores in diverse populations across various contexts. We systematically characterize a multi-ancestry type 2 diabetes polygenic risk score among 244,637 cases and 637,891 controls across diverse populations from the Population Architecture Genomics and Epidemiology Study and 13 additional biobanks and cohorts. Polygenic risk score performance is context dependent, with better performance in those who are younger, male, without hypertension, and not obese or overweight. Additionally, the polygenic risk score is associated with various diabetes-related cardiometabolic traits2025-01-01T00:00:00Z2025 Oct2026-06-04T00:36:02.233Z2026-05-03T03:12:26.12ZS-EPMC124889484103419310.1038/s41467-025-63546-4