Polygenic risk score for type 2 diabetes shows context-dependent effects across populations

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, Chris Gignoux, Kari E. North, Ruth J. F. Loos, Themistocles L. Assimes, Ulrike Peters, Charles Kooperberg, Sridharan Raghavan, Heather M. Highland and Burcu F. Darst ()
Additional contact information
Boya Guo: Fred Hutchinson Cancer Center
Yanwei Cai: Fred Hutchinson Cancer Center
Daeeun Kim: University of North Carolina at Chapel Hill
Roelof A. J. Smit: Icahn School of Medicine at Mount Sinai
Zhe Wang: Icahn School of Medicine at Mount Sinai
Kruthika R. Iyer: Gladstone Institutes
Austin T. Hilliard: VA Palo Alto Health Care System
Jeffrey Haessler: Fred Hutchinson Cancer Center
Ran Tao: Vanderbilt University Medical Center
K. Alaine Broadaway: University of North Carolina at Chapel Hill
Yujie Wang: University of North Carolina at Chapel Hill
Nikita Pozdeyev: University of Colorado Anschutz Medical Campus
Frederik F. Stæger: University of Copenhagen
Chaojie Yang: University of Virginia
Brett Vanderwerff: University of Michigan
Amit D. Patki: University of Alabama at Birmingham
Lauren Stalbow: Icahn School of Medicine at Mount Sinai
Meng Lin: University of Colorado Anschutz Medical Campus
Nicholas Rafaels: University of Colorado Anschutz Medical Campus
Jonathan Shortt: University of Colorado Anschutz Medical Campus
Laura Wiley: University of Colorado Anschutz Medical Campus
Maggie Stanislawski: University of Colorado Anschutz Medical Campus
Jack Pattee: University of Colorado Anschutz Medical Campus
Lea Davis: Icahn School of Medicine at Mount Sinai
Peter S. Straub: Vanderbilt University of Medical Center
Megan M. Shuey: Vanderbilt University of Medical Center
Nancy J. Cox: Vanderbilt University of Medical Center
Nanette R. Lee: University of San Carlos
Marit E. Jørgensen: Steno Diabetes Center Greenland
Peter Bjerregaard: University of Southern Denmark
Christina Larsen: University of Southern Denmark
Torben Hansen: University of Copenhagen
Ida Moltke: University of Copenhagen
James B. Meigs: Harvard Medical School
Daniel O. Stram: University of Southern California
Xianyong Yin: Nanjing Medical University
Xiang Zhou: University of Michigan
Kyong-Mi Chang: Corporal Michael J. Crescenz VA Medical Center
Shoa L. Clarke: Stanford University School of Medicine
Rodrigo Guarischi-Sousa: Stanford University School of Medicine
Joanna Lankester: Stanford University School of Medicine
Philip S. Tsao: Stanford University School of Medicine
Steven Buyske: Rutgers University
Mariaelisa Graff: University of North Carolina at Chapel Hill
Laura M. Raffield: University of North Carolina at Chapel Hill
Quan Sun: University of North Carolina at Chapel Hill
Lynne R. Wilkens: University of Hawaii Cancer Center
Christopher S. Carlson: Fred Hutchinson Cancer Center
Charles B. Easton: Brown University
Simin Liu: Brown University
JoAnn E. Manson: Harvard Medical School
Loïc L. Marchand: University of Hawaii Cancer Center
Christopher A. Haiman: University of Southern California
Karen L. Mohlke: University of North Carolina at Chapel Hill
Penny Gordon-Larsen: University of North Carolina at Chapel Hill
Anders Albrechtsen: University of Copenhagen
Michael Boehnke: University of Michigan
Stephen S. Rich: University of Virginia
Ani Manichaikul: University of Virginia
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Noha A. Yousri: Hamad Bin Khalifa University
Ryan M. Irvin: University of Alabama at Birmingham
Chris Gignoux: University of Colorado Anschutz Medical Campus
Kari E. North: University of North Carolina at Chapel Hill
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Themistocles L. Assimes: Stanford University School of Medicine
Ulrike Peters: Fred Hutchinson Cancer Center
Charles Kooperberg: Fred Hutchinson Cancer Center
Sridharan Raghavan: University of Colorado Anschutz Medical Campus
Heather M. Highland: University of North Carolina at Chapel Hill
Burcu F. Darst: Fred Hutchinson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63546-4

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