Boya Guo, Yanwei Cai, Daeeun Kim, Roelof A. J. Smit, Zhe Wang, Kruthika R. Iyer, Austin T. Hilliard, Jeffrey Haessler, Ran Tao, K. Alaine Broadaway, Yujie Wang, Nikita Pozdeyev, Frederik F. Stæger, Chaojie Yang, Brett Vanderwerff, Amit D. Patki, Lauren Stalbow, Meng Lin, Nicholas Rafaels, Jonathan Shortt, Laura Wiley, Maggie Stanislawski, Jack Pattee, Lea Davis, Peter S. Straub, Megan M. Shuey, Nancy J. Cox, Nanette R. Lee, Marit E. Jørgensen, Peter Bjerregaard, Christina Larsen, Torben Hansen, Ida Moltke, James B. Meigs, Daniel O. Stram, Xianyong Yin, Xiang Zhou, Kyong-Mi Chang, Shoa L. Clarke, Rodrigo Guarischi-Sousa, Joanna Lankester, Philip S. Tsao, Steven Buyske, Mariaelisa Graff, Laura M. Raffield, Quan Sun, Lynne R. Wilkens, Christopher S. Carlson, Charles B. Easton, Simin Liu, JoAnn E. Manson, Loïc L. Marchand, Christopher A. Haiman, Karen L. Mohlke, Penny Gordon-Larsen, Anders Albrechtsen, Michael Boehnke, Stephen S. Rich, Ani Manichaikul, Jerome I. Rotter, Noha A. Yousri, Ryan M. Irvin, Katy E. Trinkley, Emily B. Todd, Candace Teague, Matthew R. G. Taylor, Anna Tanaka, Carolyn T. Swartz, Kristen J. Sutton, Adrian M. Stewart, Johnathan Shortt, Hoda Sherif, Elise L. Shalowitz, Neda Rasouli, Nick Rafaels, Alaa Radwan, Ann Nadrash, Ethan Moore, Andrew Monte, Nicole L. McDaniel, David Mayer, Brianna L. Gates, James L. Martin, Darcy Marceau, Betzaida L. Maldonado, Luciana B. Vargas, Jan T. Lowery, Joe A. Lesny, Yee Ming Lee, Ethan M. Lange, Rashawnda Lacy, Elizabeth L. Kudron, Lisa Ku, Iain Konigsberg, Dave Kao, Colleen G. Julian, Randi K. Johnson, Audrey E. Hendricks, Emily Hearst, Brooke Hawkes, Casey S. Greene, Elizabeth K. Gilliland, Chris Gignoux, Hunter George, Teresa C. Frye, Alan W. Franklin, Matthew J. Fisher, Michelle N. Edelmann, Erin Culver, Jacob Crawford, Kristy Crooks, Curtis R. Coughlin, Joanne B. Cole, Emily M. Casteel, Elizabeth E. Burke, Judith Brutus-Lestin, Tonya M. Brunetti, Ian M. Brooks, Christopher H. Arehart, Kelsey Arbogast, Christina L. Aquilante, Heather D. Anderson, Henry Kranzler, Adriana Hung, Stacey B. Whitbourne, Brady Stephens, Shahpoor Alex Shayan, Luis E. Selva, Robert Ringer, Saiju Pyarajan, Scott L. DuVall, Lori Churby, Kelly Cho, Mary T. Brophy, Jessica V. Brewer, Deepak Voora, Dave Oslin, Michael Matheny, Amy Kilbourne, Elizabeth Hauser, J. Michael Gaziano, Jennifer E. Deen, Jennifer Moser, Sumitra Muralidhar, Chris Gignoux, Kari E. North, Ruth J. F. Loos, Themistocles L. Assimes, Ulrike Peters, Charles Kooperberg, Sridharan Raghavan, Heather M. Highland, Burcu F. Darst
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. © The Author(s) 2025.
Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, United States; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, United States; Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA, United States; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States; VA Palo Alto Health Care System, Palo Alto, CA, United States; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States; Vanderbilt Genetic Institute, Vanderbilt University of Medical Center, Nashville, TN, United States; Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Department of Biology, Section for Computational and RNA Biology, University of Copenhagen, Copenhagen, Denmark; Department of Genome Sciences, University of Virginia, Charlottesville, VA, United States; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States; Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States; Department of Medicine, Division of Data-Driven and Digital Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Medicine, Division of Genetic Medicine, Vanderbilt University of Medical Center, Nashville, TN, United States; USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines; Steno Diabetes Center Greenland, Nuuk, Greenland; Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Medicine, Mass General Brigham Healthcare System, Harvard Medical School, Boston, MA, United States; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States; Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States; Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States; Department of Medicine, Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States; Department of Medicine, Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, United States; Department of Genetics, Rutgers University, Piscataway, NJ, United States; Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States; Department of Epidemiology, School of Public Health, Brown University, Pawtucket, RI, United States; Department of Family Medicine, Warren Alpert Medical School, Brown University, Pawtucket, RI, United States; Department of Epidemiology, School of Public Health, Brown University, Providence, RI, United States; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States; Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Computer and Systems Engineering, Alexandria University, Alexandria, Egypt; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, United States; Department of Medicine, Division of General Internal Medicine, University of Colorado School of Medicine, Denver, CO, United States; US Department of Veterans Affair, Washington, DC, United States; US Department of Veterans Affairs, Washington, DC, United States; VA Boston Healthcare System, Boston, MA, United States; Durham VA Medical Center, Durham, NC, United States; VA Ann Arbor Healthcare System, Ann Arbor, MI, United States; VA Tennessee Valley Healthcare System, Murfreesboro, TN, United States; Philadelphia VA Medical Center, Philadelphia, PA, United States; VA Salt Lake City Health Care System, Salt Lake City, UT, United States; New Mexico VA Health Care System, Albuquerque, NM, United States; Canandaigua VA Medical Center, Canandaigua, NY, United States; VA Tennessee Valley Healthcare System, Nashville, TN, United States
