Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele

X Xinruo Zhang J Jennifer A. Brody M Mariaelisa Graff H Heather M. Highland N Nathalie Chami H Hanfei Xu Z Zhe Wang K Kendra R. Ferrier G Geetha Chittoor N Navya Shilpa Josyula M Mariah Meyer S Shreyash Gupta X Xihao Li (Department of Biostatistics) Z Zilin Li M Matthew A. Allison D Diane M. Becker L Lawrence F. Bielak J Joshua C. Bis M Meher Preethi Boorgula (University of Colorado at Denver, Denver, CO, USA.) D Donald W. Bowden J Jai G. Broome E Erin J. Buth C Christopher S. Carlson K Kyong-Mi Chang S Sameer Chavan (University of Colorado at Denver, Denver, CO, USA.) Y Yen-Feng Chiu L Lee-Ming Chuang (National Taiwan University, Taipei, Taiwan (Province of China).) M Matthew P. Conomos D Dawn L. DeMeo M Mengmeng Du R Ravindranath Duggirala C Celeste Eng A Alison E. Fohner B Barry I. Freedman M Melanie E. Garrett X Xiuqing Guo C Chris Haiman B Benjamin D. Heavner B Bertha Hidalgo J James E. Hixson Y Yuk-Lam Ho B Brian D. Hobbs D Donglei Hu Q Qin Hui C Chii-Min Hwu R Rebecca D. Jackson D Deepti Jain (University of Washington, Seattle, WA, USA.) R Rita R. Kalyani S Sharon L. R. Kardia T Tanika N. Kelly E Ethan M. Lange M Michael LeNoir C Changwei Li M Merry-Lynn N. McDonald C Caitlin P. McHugh A Alanna C. Morrison T Take Naseri L Loic Le Marchand J Jeffrey O’Connell C Christopher J. O’Donnell N Nicholette D. Palmer J James S. Pankow J James A. Perry U Ulrike Peters (Fred Hutchinson Cancer Research Center, Seattle, WA, USA.) M Michael H. Preuss D D. C. Rao E Elizabeth A. Regan S Sefuiva M. Reupena D Dan M. Roden J Jose Rodriguez-Santana C Colleen M. Sitlani J Jennifer A. Smith H Hemant K. Tiwari R Ramachandran S. Vasan (Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.) Z Zeyuan Wang D Daniel E. Weeks J Jennifer Wessel (Indiana University, Indianapolis, IN, USA.) K Kerri L. Wiggins L Lynne R. Wilkens P Peter W. F. Wilson L Lisa R. Yanek Z Zachary T. Yoneda W Wei Zhao S Sebastian Zöllner (Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.) D Donna K. Arnett A Allison E. Ashley-Koch K Kathleen C. Barnes J John Blangero E Eric Boerwinkle E Esteban G. Burchard A April P. Carson D Daniel I. Chasman Y Yii-Der Ida Chen J Joanne E. Curran M Myriam Fornage V Victor R. Gordeuk J Jiang He S Susan R. Heckbert L Lifang Hou M Marguerite R. Irvin C Charles Kooperberg (Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.) R Ryan L. Minster B Braxton D. Mitchell M Mehdi Nouraie B Bruce M. Psaty L Laura M. Raffield (Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.) A Alexander P. Reiner S Stephen S. Rich (Department of Genome Sciences, School of Medicine, University of Virginia, Charlottesville, VA, USA.) J Jerome I. Rotter M M. Benjamin Shoemaker N Nicholas L. Smith K Kent D. Taylor (The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.) M Marilyn J. Telen S Scott T. Weiss Y Yingze Zhang N Nancy Heard-Costa (Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.) Y Yan V. Sun X Xihong Lin L L. Adrienne Cupples (Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.) L Leslie A. Lange C Ching-Ti Liu (Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.) R Ruth J. F. Loos K Kari E. North A Anne E. Justice

Abstract

Abstract Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( P  < 5 × 10 − 9 ), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

Article Details

Volume / Issue Vol. 16, Issue 1
Published April 11, 2025
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (124)

X

Xinruo Zhang

J

Jennifer A. Brody

M

Mariaelisa Graff

H

Heather M. Highland

N

Nathalie Chami

H

Hanfei Xu

Z

Zhe Wang

K

Kendra R. Ferrier

G

Geetha Chittoor

N

Navya Shilpa Josyula

M

Mariah Meyer

S

Shreyash Gupta

X

Xihao Li

Department of Biostatistics

Z

Zilin Li

M

Matthew A. Allison

D

Diane M. Becker

L

Lawrence F. Bielak

J

Joshua C. Bis

M

Meher Preethi Boorgula

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

D

Donald W. Bowden

J

Jai G. Broome

E

Erin J. Buth

C

Christopher S. Carlson

K

Kyong-Mi Chang

S

Sameer Chavan

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

Y

Yen-Feng Chiu

L

Lee-Ming Chuang

National Taiwan University, Taipei, Taiwan (Province of China).

M

Matthew P. Conomos

D

Dawn L. DeMeo

M

Mengmeng Du

R

Ravindranath Duggirala

C

Celeste Eng

A

Alison E. Fohner

B

Barry I. Freedman

M

Melanie E. Garrett

X

Xiuqing Guo

C

Chris Haiman

B

Benjamin D. Heavner

B

Bertha Hidalgo

J

James E. Hixson

Y

Yuk-Lam Ho

B

Brian D. Hobbs

D

Donglei Hu

Q

Qin Hui

C

Chii-Min Hwu

R

Rebecca D. Jackson

D

Deepti Jain

University of Washington, Seattle, WA, USA.

R

Rita R. Kalyani

S

Sharon L. R. Kardia

T

Tanika N. Kelly

E

Ethan M. Lange

M

Michael LeNoir

C

Changwei Li

M

Merry-Lynn N. McDonald

C

Caitlin P. McHugh

A

Alanna C. Morrison

T

Take Naseri

L

Loic Le Marchand

J

Jeffrey O’Connell

C

Christopher J. O’Donnell

N

Nicholette D. Palmer

J

James S. Pankow

J

James A. Perry

U

Ulrike Peters

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

M

Michael H. Preuss

D

D. C. Rao

E

Elizabeth A. Regan

S

Sefuiva M. Reupena

D

Dan M. Roden

J

Jose Rodriguez-Santana

C

Colleen M. Sitlani

J

Jennifer A. Smith

H

Hemant K. Tiwari

R

Ramachandran S. Vasan

Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.

Z

Zeyuan Wang

D

Daniel E. Weeks

J

Jennifer Wessel

Indiana University, Indianapolis, IN, USA.

K

Kerri L. Wiggins

L

Lynne R. Wilkens

P

Peter W. F. Wilson

L

Lisa R. Yanek

Z

Zachary T. Yoneda

W

Wei Zhao

S

Sebastian Zöllner

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

D

Donna K. Arnett

A

Allison E. Ashley-Koch

K

Kathleen C. Barnes

J

John Blangero

E

Eric Boerwinkle

E

Esteban G. Burchard

A

April P. Carson

D

Daniel I. Chasman

Y

Yii-Der Ida Chen

J

Joanne E. Curran

M

Myriam Fornage

V

Victor R. Gordeuk

J

Jiang He

S

Susan R. Heckbert

L

Lifang Hou

M

Marguerite R. Irvin

C

Charles Kooperberg

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

R

Ryan L. Minster

B

Braxton D. Mitchell

M

Mehdi Nouraie

B

Bruce M. Psaty

L

Laura M. Raffield

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

A

Alexander P. Reiner

S

Stephen S. Rich

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

J

Jerome I. Rotter

M

M. Benjamin Shoemaker

N

Nicholas L. Smith

K

Kent D. Taylor

The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.

M

Marilyn J. Telen

S

Scott T. Weiss

Y

Yingze Zhang

N

Nancy Heard-Costa

Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA.

Y

Yan V. Sun

X

Xihong Lin

L

L. Adrienne Cupples

Framingham Heart Study, National Heart, Lung, and Blood Institute, National Institutes of Health and Boston University, Framingham, MA, USA.

L

Leslie A. Lange

C

Ching-Ti Liu

Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.

R

Ruth J. F. Loos

K

Kari E. North

A

Anne E. Justice