Polygenic risk scores (PRS) hold prognostic value for identifying individuals at higher risk of type 2 diabetes (T2D). However, further characterization is needed to understand the generalizability of T2D PRS in diverse populations across various contexts. We characterized a multi-ancestry T2D PRS among 244,637 cases and 637,891 controls across eight populations from the Population Architecture Genomics and Epidemiology (PAGE) Study and 13 additional biobanks and cohorts. PRS performance was context dependent, with better performance in those who were younger, male, with a family history of T2D, without hypertension, and not obese or overweight. Additionally, the PRS was associated with various diabetes-related cardiometabolic traits and T2D complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between T2D and other diseases. These findings highlight the need to account for context when evaluating PRS as a tool for T2D risk prognostication and potentially generalizable associations of T2D PRS with diabetes-related traits despite differential performance in T2D prediction across diverse populations.

R.J.F.L. has acted as a member of advisory boards and as a speaker for Ely Lilly and the novo Nordisk Foundation, for which she has received fees. L.M.R is a consultant for the NHLBI TOPMed Administrative Coordinating Center (through Westat). U.P. was a consultant with AbbVie and her husband holds individual stocks for the following companies: BioNTech SE-ADR, Amazon, CureVac BV, Google/Alphabet Inc Class C, NVIDIA Corp, Microsoft Corp.

This work was supported by the National Institutes of Health (R01HL151152 to C.K., C.G., and K.E.N., R00CA246063, R03CA287235, and U01CA261339 to B.F.D., R01HL143885 and R01DK139598 to P.G.L. and K.E.N., R01HL163262, R01DK122503, and R01HL142302 to K.E.N., UM1DK078616 to C.K., R01HD30880 and R01AG065357 to P.G.L., R01DK124097, R01HL156991, and R01DK123019 to R.J.F.L.), an award from the Andy Hill Cancer Research Endowment Distinguished Researchers Program (B.F.D.), and a Fred Hutchinson Cancer Center Translational Data Science New Collaboration Award (B.F.D). R.J.F.L. is supported by grants from the Novo Nordisk Foundation (NNF20OC0059313, NNF23SA0084103, and NNF18CC0034900). Work done by N.A.Y. was made possible by PPM2 grant PPM20226170020 from the Qatar National Research Fund (QNRF) and Qatar Genome Program (QGP) (members of Qatar Foundation) and by NPRPS11 grant NPRP11S0114180299 from the Qatar National Research Fund. The findings herein reflect the work and are solely the responsibility of the author. Funders did not contribute to design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All methods were carried out in accordance with relevant guidelines and regulations. Individual studies were approved by the appropriate institutional review boards (IRB) and written informed consent was obtained from all participants.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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The Ge et al. T2D PRS and the T2D PRS of 582 variants are available on the PGS Catalog (https://www.pgscatalog.org; PGS IDs: PGS002308 and PGS000804, respectively). The newly generated PRS in this study will be published on the PGS Catalog. GWAS summary statistics from the Mahajan et al. 2022 study are available on the DIAGRAM consortium website (http://diagram-consortium.org). GWAS summary statistics from the Vujkovic et al., 2020 study are available on dbGaP (accession numbers pha004945.1, pha004943.1, pha004946.1, and pha004944.1, respectively). LD matrices used for PRS-CSx are available at https://github.com/getian107/PRScsx.