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

B Boya Guo Y Yanwei Cai D DaeEun Kim R Roelof A. J. Smit Z Zhe Wang K Kruthika R. Iyer A Austin T. Hilliard J Jeffrey Haessler R Ran Tao K K. Alaine Broadaway Y Yujie Wang (Shenyang National Laboratory for Materials Science, Institute of Metal Research) N Nikita Pozdeyev F Frederik F. Stæger C Chaojie Yang B Brett Vanderwerff A Amit D. Patki L Lauren Stalbow M Meng Lin N Nicholas Rafaels (University of Colorado at Denver, Denver, CO, USA.) J Jonathan Shortt L Laura Wiley M Maggie Stanislawski J Jack Pattee L Lea Davis P Peter S. Straub M Megan M. Shuey N Nancy J. Cox N Nanette R. Lee M Marit E. Jørgensen P Peter Bjerregaard C Christina Larsen T Torben Hansen I Ida Moltke J James B. Meigs D Daniel O. Stram X Xianyong Yin X Xiang Zhou K Kyong-Mi Chang S Shoa L. Clarke R Rodrigo Guarischi-Sousa J Joanna Lankester P Philip S. Tsao S Steven Buyske M Mariaelisa Graff L Laura M. Raffield (Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.) Q Quan Sun L Lynne R. Wilkens C Christopher S. Carlson C Charles B. Easton S Simin Liu (Brown University, Providence, RI, USA.) J JoAnn E. Manson L Loïc L. Marchand C Christopher A. Haiman K Karen L. Mohlke P Penny Gordon-Larsen A Anders Albrechtsen M Michael Boehnke S Stephen S. Rich (Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.) A Ani Manichaikul (Department of Genome Sciences, Center for Public Health Genomics, University of Virginia) J Jerome I. Rotter N Noha A. Yousri R Ryan M. Irvin H Heather D. Anderson C Christina L. Aquilante K Kelsey Arbogast C Christopher H. Arehart I Ian M. Brooks T Tonya M. Brunetti J Judith Brutus-Lestin E Elizabeth E. Burke E Emily M. Casteel J Joanne B. Cole C Curtis R. Coughlin K Kristy Crooks J Jacob Crawford E Erin Culver M Michelle N. Edelmann M Matthew J. Fisher A Alan W. Franklin T Teresa C. Frye H Hunter George E Elizabeth K. Gilliland C Casey S. Greene B Brooke Hawkes E Emily Hearst A Audrey E. Hendricks R Randi K. Johnson C Colleen G. Julian D Dave Kao I Iain Konigsberg L Lisa Ku E Elizabeth L. Kudron R Rashawnda Lacy E Ethan M. Lange Y Yee Ming Lee J Joe A. Lesny J Jan T. Lowery L Luciana B. Vargas B Betzaida L. Maldonado D Darcy Marceau J James L. Martin B Brianna L. Gates D David Mayer N Nicole L. McDaniel A Andrew Monte E Ethan Moore A Ann Nadrash A Alaa Radwan N Nick Rafaels N Neda Rasouli E Elise L. Shalowitz H Hoda Sherif J Johnathan Shortt A Adrian M. Stewart K Kristen J. Sutton C Carolyn T. Swartz A Anna Tanaka M Matthew R. G. Taylor (Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.) C Candace Teague E Emily B. Todd K Katy E. Trinkley L Laura K. Wiley S Sumitra Muralidhar J Jennifer Moser J Jennifer E. Deen J J. Michael Gaziano E Elizabeth Hauser A Amy Kilbourne M Michael Matheny D Dave Oslin D Deepak Voora J Jessica V. Brewer M Mary T. Brophy K Kelly Cho (Million Veteran Program Coordinating Center) L Lori Churby S Scott L. DuVall S Saiju Pyarajan R Robert Ringer L Luis E. Selva S Shahpoor Alex Shayan B Brady Stephens S Stacey B. Whitbourne A Adriana Hung H Henry Kranzler C Chris Gignoux (Stanford University, Stanford, CA, USA.) K Kari E. North R Ruth J. F. Loos T Themistocles L. Assimes U Ulrike Peters (Fred Hutchinson Cancer Research Center, Seattle, WA, USA.) C Charles Kooperberg (Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.) S Sridharan Raghavan H Heather M. Highland B Burcu F. Darst

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.

Article Details

Volume / Issue Vol. 16, Issue 1
Published October 01, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (153)

B

Boya Guo

Y

Yanwei Cai

D

DaeEun Kim

R

Roelof A. J. Smit

Z

Zhe Wang

K

Kruthika R. Iyer

A

Austin T. Hilliard

J

Jeffrey Haessler

R

Ran Tao

K

K. Alaine Broadaway

Y

Yujie Wang

Shenyang National Laboratory for Materials Science, Institute of Metal Research

N

Nikita Pozdeyev

F

Frederik F. Stæger

C

Chaojie Yang

B

Brett Vanderwerff

A

Amit D. Patki

L

Lauren Stalbow

M

Meng Lin

N

Nicholas Rafaels

University of Colorado at Denver, Denver, CO, USA.

J

Jonathan Shortt

L

Laura Wiley

M

Maggie Stanislawski

J

Jack Pattee

L

Lea Davis

P

Peter S. Straub

M

Megan M. Shuey

N

Nancy J. Cox

N

Nanette R. Lee

M

Marit E. Jørgensen

P

Peter Bjerregaard

C

Christina Larsen

T

Torben Hansen

I

Ida Moltke

J

James B. Meigs

D

Daniel O. Stram

X

Xianyong Yin

X

Xiang Zhou

K

Kyong-Mi Chang

S

Shoa L. Clarke

R

Rodrigo Guarischi-Sousa

J

Joanna Lankester

P

Philip S. Tsao

S

Steven Buyske

M

Mariaelisa Graff

L

Laura M. Raffield

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Q

Quan Sun

L

Lynne R. Wilkens

C

Christopher S. Carlson

C

Charles B. Easton

S

Simin Liu

Brown University, Providence, RI, USA.

J

JoAnn E. Manson

L

Loïc L. Marchand

C

Christopher A. Haiman

K

Karen L. Mohlke

P

Penny Gordon-Larsen

A

Anders Albrechtsen

M

Michael Boehnke

S

Stephen S. Rich

Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.

A

Ani Manichaikul

Department of Genome Sciences, Center for Public Health Genomics, University of Virginia

J

Jerome I. Rotter

N

Noha A. Yousri

R

Ryan M. Irvin

H

Heather D. Anderson

C

Christina L. Aquilante

K

Kelsey Arbogast

C

Christopher H. Arehart

I

Ian M. Brooks

T

Tonya M. Brunetti

J

Judith Brutus-Lestin

E

Elizabeth E. Burke

E

Emily M. Casteel

J

Joanne B. Cole

C

Curtis R. Coughlin

K

Kristy Crooks

J

Jacob Crawford

E

Erin Culver

M

Michelle N. Edelmann

M

Matthew J. Fisher

A

Alan W. Franklin

T

Teresa C. Frye

H

Hunter George

E

Elizabeth K. Gilliland

C

Casey S. Greene

B

Brooke Hawkes

E

Emily Hearst

A

Audrey E. Hendricks

R

Randi K. Johnson

C

Colleen G. Julian

D

Dave Kao

I

Iain Konigsberg

L

Lisa Ku

E

Elizabeth L. Kudron

R

Rashawnda Lacy

E

Ethan M. Lange

Y

Yee Ming Lee

J

Joe A. Lesny

J

Jan T. Lowery

L

Luciana B. Vargas

B

Betzaida L. Maldonado

D

Darcy Marceau

J

James L. Martin

B

Brianna L. Gates

D

David Mayer

N

Nicole L. McDaniel

A

Andrew Monte

E

Ethan Moore

A

Ann Nadrash

A

Alaa Radwan

N

Nick Rafaels

N

Neda Rasouli

E

Elise L. Shalowitz

H

Hoda Sherif

J

Johnathan Shortt

A

Adrian M. Stewart

K

Kristen J. Sutton

C

Carolyn T. Swartz

A

Anna Tanaka

M

Matthew R. G. Taylor

Department of Medicine, Adult Medical Genetics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

C

Candace Teague

E

Emily B. Todd

K

Katy E. Trinkley

L

Laura K. Wiley

S

Sumitra Muralidhar

J

Jennifer Moser

J

Jennifer E. Deen

J

J. Michael Gaziano

E

Elizabeth Hauser

A

Amy Kilbourne

M

Michael Matheny

D

Dave Oslin

D

Deepak Voora

J

Jessica V. Brewer

M

Mary T. Brophy

K

Kelly Cho

Million Veteran Program Coordinating Center

L

Lori Churby

S

Scott L. DuVall

S

Saiju Pyarajan

R

Robert Ringer

L

Luis E. Selva

S

Shahpoor Alex Shayan

B

Brady Stephens

S

Stacey B. Whitbourne

A

Adriana Hung

H

Henry Kranzler

C

Chris Gignoux

Stanford University, Stanford, CA, USA.

K

Kari E. North

R

Ruth J. F. Loos

T

Themistocles L. Assimes

U

Ulrike Peters

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

C

Charles Kooperberg

Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.

S

Sridharan Raghavan

H

Heather M. Highland

B

Burcu F. Darst