ArticleNature communications2025
Polygenic risk score for type 2 diabetes shows context-dependent effects across populations.
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Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9citing papers in PubMed
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Who cites it
9 citing papers in PubMed.
- Polygenic risk scores in human genetics for study design discovery and translation.Human genetics · 2026Review
- Polygenic risk scores, adiposity, and disease transition in type 2 diabetes and colorectal cancer comorbidity: a population-based Chinese cohort study.BMC cancer · 2026Observational
- Predominantly genetic, intrauterine, and lifestyle aetiologies of type 2 diabetes are associated with distinct clinical presentations and risk of complications: a Danish cross-sectional and follow-up study.EClinicalMedicine · 2026Article
- Quantifying the utility of type 2 diabetes polygenic risk score for predicting incident diabetes: an analysis of large US-based cohort studies.BMC medical genomics · 2026Article
- Review
- Toll-Like Receptors in Diabetes: Immunometabolic Mechanisms and Emerging Precision Therapeutic Strategies.Journal of inflammation research · 2026Review
- Polygenic risk score translation across diverse populations.Frontiers in cardiovascular medicine · 2026Review
- Central adiposity and sex influence lipid and glucose indices in Mexican adults: implications for metabolic risk assessment.Frontiers in nutrition · 2026Article
- Review
Corrections and comments
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Authors and funding
73 authors.
Boya GuoPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. bguo@fredhutch.org.ORCID http://orcid.org/0000-0002-8508-4084
Yanwei CaiPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Daeeun KimDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-9387-0739
Roelof A J SmitThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Zhe WangThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-8046-4969
Kruthika R IyerData Science and Biotechnology, Gladstone Institutes, San Francisco, CA, USA.
Austin T HilliardVA Palo Alto Health Care System, Palo Alto, CA, USA.ORCID http://orcid.org/0000-0002-1289-4377
Jeffrey HaesslerPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Ran TaoDepartment of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.ORCID http://orcid.org/0000-0002-1106-2923
K Alaine BroadawayDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Yujie WangDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-1087-2182
Nikita PozdeyevColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0001-8574-1972
Frederik F StægerDepartment of Biology, Section for Computational and RNA Biology, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0002-2295-8637
Chaojie YangDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0001-6782-1389
Brett VanderwerffDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
Amit D PatkiDepartment of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
Lauren StalbowThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Meng LinColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Nicholas RafaelsColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Jonathan ShorttColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-7980-5420
Laura WileyColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0001-6681-9754
Maggie StanislawskiColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0001-7768-8868
Jack PatteeDepartment of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Lea DavisDepartment of Medicine, Division of Data-Driven and Digital Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0001-5143-2282
Peter S StraubVanderbilt Genetic Institute, Vanderbilt University of Medical Center, Nashville, TN, USA.
Megan M ShueyVanderbilt Genetic Institute, Vanderbilt University of Medical Center, Nashville, TN, USA.ORCID http://orcid.org/0000-0003-2866-3562
Nancy J CoxVanderbilt Genetic Institute, Vanderbilt University of Medical Center, Nashville, TN, USA.
Nanette R LeeUSC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines.
Marit E JørgensenSteno Diabetes Center Greenland, Nuuk, Greenland.ORCID http://orcid.org/0000-0001-8356-5565
Peter BjerregaardCentre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.ORCID http://orcid.org/0000-0001-7153-8447
Christina LarsenCentre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
Torben HansenNovo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0001-8748-3831
Ida MoltkeDepartment of Biology, Section for Computational and RNA Biology, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0001-7052-8554
James B MeigsDepartment of Medicine, Mass General Brigham Healthcare System, Harvard Medical School, Boston, MA, USA.
Daniel O StramDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Xianyong YinDepartment of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.ORCID http://orcid.org/0000-0001-6454-2384
Xiang ZhouDepartment of Biostatistics, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-4331-7599
Kyong-Mi ChangCorporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0001-6811-9364
Shoa L ClarkeDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-6592-1172
Rodrigo Guarischi-SousaDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0002-3614-9996
Joanna LankesterDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Philip S TsaoDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0001-7274-9318
Steven BuyskeDepartment of Genetics, Rutgers University, Piscataway, NJ, USA.ORCID http://orcid.org/0000-0001-8539-5416
Mariaelisa GraffDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-6380-1735
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-7892-193X
Quan SunDepartment of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-8324-2803
Lynne R WilkensEpidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
Christopher S CarlsonPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Charles B EastonDepartment of Epidemiology, School of Public Health, Brown University, Pawtucket, RI, USA.
Simin LiuDepartment of Epidemiology, School of Public Health, Brown University, Providence, RI, USA.ORCID http://orcid.org/0000-0003-2098-3844
JoAnn E MansonDepartment of Medicine, Mass General Brigham Healthcare System, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9426-7595
Loïc L MarchandEpidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
Christopher A HaimanDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.ORCID http://orcid.org/0000-0002-0097-9971
Karen L MohlkeDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-6721-153X
Penny Gordon-LarsenDepartment of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-5322-4188
Anders AlbrechtsenDepartment of Biology, Section for Computational and RNA Biology, University of Copenhagen, Copenhagen, Denmark.ORCID http://orcid.org/0000-0001-7306-031X
Michael BoehnkeDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-6442-7754
Stephen S RichDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0003-3872-7793
Ani ManichaikulDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0002-5998-795X
Jerome I RotterDepartment of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0001-7191-1723
Noha A YousriCollege of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Ryan M IrvinDepartment of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.
biobank at the Colorado Center for Personalized Medicine (CCPM)
VA Million Veteran Program (MVP)
Chris GignouxColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0001-9728-6567
Kari E NorthDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-8903-0366
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-8532-5087
Themistocles L AssimesDepartment of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.ORCID http://orcid.org/0000-0003-2349-0009
Ulrike PetersPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-5666-9318
Charles KooperbergPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7986-8560
Sridharan RaghavanColorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Heather M HighlandDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-3583-8239
Burcu F DarstPublic Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA. bdarst@fredhutch.org.ORCID http://orcid.org/0000-0002-6205-4632
Funding
Translational Bioimaging Core Shared ResourceP30CA015704 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Marian Esvelt · 1985 to 2026
$296.4MTRANSCRIPTOME AND PROTEOME STRATIFICATION OF PROSTATE ADENOCARCINOMA PHENOTYPESP50CA097186 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI John Kyung Lee · 2002 to 2026
$58.1MUniversity of Hawaii Cancer Center CCSGP30CA071789 · NCI · UNIVERSITY OF HAWAII AT MANOA · PI Xin Chen · 1996 to 2026
$56.2MMONITORING SOCIAL CHANGE: HEALTH, REPRODUCTION, AGINGR01HD030880 · NICHD · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ADAIR, LINDA S, POPKIN, BARRY M · 1994 to 2024
$27.0MRegional Pilot And Feasibility Study Grants ProgramP30DK020572 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Mehboob A Hussain · 2013 to 2026
$24.3MPolygenic Risk Scores for Diverse Populations - Bridging Research and Clinical CareR01HL151152 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI Christy Leigh Avery, Jennifer Below · 2020 to 2026
$12.3MPacific Center for Genome ResearchU54HG013243 · NHGRI · UNIVERSITY OF HAWAII AT MANOA · PI Youping Deng · 2023 to 2026
$10.8MLeveraging multi-omics approaches to examine metabolic challenges of obesity in relation to cardiovascular diseasesR01HL143885 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI AVERY, CHRISTY LEIGH, GORDON-LARSEN, PENNY · 2019 to 2022
$8.9MA Multi-Ancestry Study of Gene-Lifestyle Interactions and Multi-Omics in Cardiometabolic TraitsR01HL156991 · NHLBI · WASHINGTON UNIVERSITY · PI RAO, DABEERU C · 2021 to 2024
$8.8MHispanic Latino Lipid ConsortiumR01HL142302 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Jennifer Below, JOSEPH MCCORMICK · 2018 to 2026
$5.8MLeveraging Prospective Cancer Epidemiology Cohorts and Novel Methods to Improve Polygenic Risk ScoresU01CA261339 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Fei Chen, David V Conti · 2021 to 2026
$5.2MIntegrative Approaches to Identifying Function and Clinical Significance of Adiposity Susceptibility GenesR01DK122503 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Anne Justice, Ching-Ti Liu · 2020 to 2026
$4.5MBLRD VA I01 BX003362NCI NIH HHS P30 CA015704NCI NIH HHS P30 CA071789NCI NIH HHS P50 CA097186NCI NIH HHS R00 CA246063NCI NIH HHS R03 CA287235NCI NIH HHS U01 CA261339NHGRI NIH HHS R01 HG011432NHGRI NIH HHS U54 HG013243NHLBI NIH HHS R01 HL142302NHLBI NIH HHS R01 HL143885NHLBI NIH HHS R01 HL151152NHLBI NIH HHS R01 HL156991NHLBI NIH HHS R01 HL163262NHLBI NIH HHS R01 HL174378NIA NIH HHS R01 AG065357NICHD NIH HHS R01 HD030880NIDDK NIH HHS P30 DK020572NIDDK NIH HHS R01 DK122503NIDDK NIH HHS R01 DK123019NIDDK NIH HHS R01 DK124097NIDDK NIH HHS R01 DK139598NIDDK NIH HHS UM1 DK078616Novo Nordisk Fonden (Novo Nordisk Foundation) NNF18CC0034900Novo Nordisk Fonden (Novo Nordisk Foundation) NNF20OC0059313Qatar National Research Fund (QNRF) NPRP11S-0114-180299Qatar National Research Fund (QNRF) PPM2-0226-170020U.S. Department of Health & Human Services | National Institutes of Health (NIH) R00CA246063U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DK122503U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DK123019U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DK139598U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HD30880U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HL142302U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HL143885U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HL151152U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HL156991U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HL163262U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01HL174378U.S. Department of Health & Human Services | National Institutes of Health (NIH) R03CA287235U.S. Department of Health & Human Services | National Institutes of Health (NIH) U01CA261339U.S. Department of Health & Human Services | National Institutes of Health (NIH) U54HG013243U.S. Department of Health & Human Services | National Institutes of Health (NIH) UM1DK078616U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P30CA015704U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P50CA097186
Abstract
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 traits and type 2 diabetes complications, suggesting its utility for stratifying risk of complications and identifying shared genetic architecture between type 2 diabetes and other diseases. These findings highlight the need to account for context when evaluating polygenic risk score as a tool for type 2 diabetes risk prognostication and the potentially generalizable associations of type 2 diabetes polygenic risk score with diabetes-related traits, despite differential performance in type 2 diabetes prediction across diverse populations. Our study provides a comprehensive resource to characterize a type 2 diabetes polygenic risk score.
Indexed as
Diabetes Mellitus, Type 2Genetic Predisposition to DiseaseMultifactorial InheritanceAdultAgedCase-Control StudiesFemaleGenetic Risk ScoreGenome-Wide Association StudyHumansMaleMiddle AgedPolymorphism, Single NucleotideRisk Factors
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