Nature Communications (Apr 2025)
Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele
- Xinruo Zhang,
- Jennifer A. Brody,
- Mariaelisa Graff,
- Heather M. Highland,
- Nathalie Chami,
- Hanfei Xu,
- Zhe Wang,
- Kendra R. Ferrier,
- Geetha Chittoor,
- Navya Shilpa Josyula,
- Mariah Meyer,
- Shreyash Gupta,
- Xihao Li,
- Zilin Li,
- Matthew A. Allison,
- Diane M. Becker,
- Lawrence F. Bielak,
- Joshua C. Bis,
- Meher Preethi Boorgula,
- Donald W. Bowden,
- Jai G. Broome,
- Erin J. Buth,
- Christopher S. Carlson,
- Kyong-Mi Chang,
- Sameer Chavan,
- Yen-Feng Chiu,
- Lee-Ming Chuang,
- Matthew P. Conomos,
- Dawn L. DeMeo,
- Mengmeng Du,
- Ravindranath Duggirala,
- Celeste Eng,
- Alison E. Fohner,
- Barry I. Freedman,
- Melanie E. Garrett,
- Xiuqing Guo,
- Chris Haiman,
- Benjamin D. Heavner,
- Bertha Hidalgo,
- James E. Hixson,
- Yuk-Lam Ho,
- Brian D. Hobbs,
- Donglei Hu,
- Qin Hui,
- Chii-Min Hwu,
- Rebecca D. Jackson,
- Deepti Jain,
- Rita R. Kalyani,
- Sharon L. R. Kardia,
- Tanika N. Kelly,
- Ethan M. Lange,
- Michael LeNoir,
- Changwei Li,
- Loic Le Marchand,
- Merry-Lynn N. McDonald,
- Caitlin P. McHugh,
- Alanna C. Morrison,
- Take Naseri,
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium,
- Jeffrey O’Connell,
- Christopher J. O’Donnell,
- Nicholette D. Palmer,
- James S. Pankow,
- James A. Perry,
- Ulrike Peters,
- Michael H. Preuss,
- D. C. Rao,
- Elizabeth A. Regan,
- Sefuiva M. Reupena,
- Dan M. Roden,
- Jose Rodriguez-Santana,
- Colleen M. Sitlani,
- Jennifer A. Smith,
- Hemant K. Tiwari,
- Ramachandran S. Vasan,
- Zeyuan Wang,
- Daniel E. Weeks,
- Jennifer Wessel,
- Kerri L. Wiggins,
- Lynne R. Wilkens,
- Peter W. F. Wilson,
- Lisa R. Yanek,
- Zachary T. Yoneda,
- Wei Zhao,
- Sebastian Zöllner,
- Donna K. Arnett,
- Allison E. Ashley-Koch,
- Kathleen C. Barnes,
- John Blangero,
- Eric Boerwinkle,
- Esteban G. Burchard,
- April P. Carson,
- Daniel I. Chasman,
- Yii-Der Ida Chen,
- Joanne E. Curran,
- Myriam Fornage,
- Victor R. Gordeuk,
- Jiang He,
- Susan R. Heckbert,
- Lifang Hou,
- Marguerite R. Irvin,
- Charles Kooperberg,
- Ryan L. Minster,
- Braxton D. Mitchell,
- Mehdi Nouraie,
- Bruce M. Psaty,
- Laura M. Raffield,
- Alexander P. Reiner,
- Stephen S. Rich,
- Jerome I. Rotter,
- M. Benjamin Shoemaker,
- Nicholas L. Smith,
- Kent D. Taylor,
- Marilyn J. Telen,
- Scott T. Weiss,
- Yingze Zhang,
- Nancy Heard-Costa,
- Yan V. Sun,
- Xihong Lin,
- L. Adrienne Cupples,
- Leslie A. Lange,
- Ching-Ti Liu,
- Ruth J. F. Loos,
- Kari E. North,
- Anne E. Justice
Affiliations
- Xinruo Zhang
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Jennifer A. Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Mariaelisa Graff
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Heather M. Highland
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Nathalie Chami
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Hanfei Xu
- Department of Biostatistics, School of Public Health, Boston University
- Zhe Wang
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Kendra R. Ferrier
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Anschutz Medical Campus
- Geetha Chittoor
- Population Health Sciences, Geisinger
- Navya Shilpa Josyula
- Population Health Sciences, Geisinger
- Mariah Meyer
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Anschutz Medical Campus
- Shreyash Gupta
- Population Health Sciences, Geisinger
- Xihao Li
- Department of Biostatistics, Harvard T.H. Chan School of Public Health
- Zilin Li
- Biostatistics and Health Data Science, Indiana University School of Medicine
- Matthew A. Allison
- Department of Family Medicine, Division of Preventive Medicine, The University of California San Diego
- Diane M. Becker
- Department of Medicine, General Internal Medicine, Johns Hopkins University School of Medicine
- Lawrence F. Bielak
- Department of Epidemiology, School of Public Health, University of Michigan
- Joshua C. Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Meher Preethi Boorgula
- Department of Medicine, University of Colorado School of Medicine
- Donald W. Bowden
- Department of Biochemistry, Wake Forest School of Medicine
- Jai G. Broome
- Department of Biostatistics, School of Public Health, University of Washington
- Erin J. Buth
- Department of Biostatistics, School of Public Health, University of Washington
- Christopher S. Carlson
- Division of Public Health Sciences, Fred Hutchinson Cancer Center
- Kyong-Mi Chang
- The Corporal Michael J. Crescenz VA Medical Center
- Sameer Chavan
- Department of Medicine, University of Colorado School of Medicine
- Yen-Feng Chiu
- Institute of Population Health Sciences, National Health Research Institutes
- Lee-Ming Chuang
- Department of Internal Medicine, Division of Metabolism/Endocrinology, National Taiwan University Hospital
- Matthew P. Conomos
- Department of Biostatistics, School of Public Health, University of Washington
- Dawn L. DeMeo
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
- Mengmeng Du
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center
- Ravindranath Duggirala
- Life Sciences, College of Arts and Sciences, Texas A&M University-San Antonio
- Celeste Eng
- Department of Medicine, Lung Biology Center, University of California, San Francisco
- Alison E. Fohner
- Epidemiology, Institute of Public Health Genetics, School of Public Health, University of Washington
- Barry I. Freedman
- Internal Medicine, Section on Nephrology, Wake Forest School of Medicine
- Melanie E. Garrett
- Duke Molecular Physiology Institute, Duke University Medical Center
- Xiuqing Guo
- Department of Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Chris Haiman
- Preventive Medicine, Keck School of Medicine, University of Southern California
- Benjamin D. Heavner
- Department of Biostatistics, School of Public Health, University of Washington
- Bertha Hidalgo
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham School of Public Health
- James E. Hixson
- Department of Epidemiology, School of Public Health, UTHealth Houston
- Yuk-Lam Ho
- Veterans Affairs Boston Healthcare System
- Brian D. Hobbs
- Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School
- Donglei Hu
- Department of Medicine, Lung Biology Center, University of California, San Francisco
- Qin Hui
- Department of Epidemiology, Emory University Rollins School of Public Health
- Chii-Min Hwu
- Department of Medicine, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital
- Rebecca D. Jackson
- Endocrinology, Ohio State University
- Deepti Jain
- Department of Biostatistics, School of Public Health, University of Washington
- Rita R. Kalyani
- Department of Medicine, Endocrinology, Johns Hopkins University School of Medicine
- Sharon L. R. Kardia
- Department of Epidemiology, School of Public Health, University of Michigan
- Tanika N. Kelly
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University
- Ethan M. Lange
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Anschutz Medical Campus
- Michael LeNoir
- Department of Pediatrics, Bay Area Pediatrics
- Changwei Li
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University
- Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center
- Merry-Lynn N. McDonald
- Department of Medicine, Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham
- Caitlin P. McHugh
- Department of Biostatistics, School of Public Health, University of Washington
- Alanna C. Morrison
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- Take Naseri
- Naseri & Associates Public Health Consultancy Firm and Family Health Clinic
- NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
- Jeffrey O’Connell
- Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland
- Christopher J. O’Donnell
- Veterans Affairs Boston Healthcare System
- Nicholette D. Palmer
- Department of Biochemistry, Wake Forest School of Medicine
- James S. Pankow
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota
- James A. Perry
- Department of Medicine, School of Medicine, University of Maryland
- Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Center
- Michael H. Preuss
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- D. C. Rao
- Center for Biostatistics and Data Science, Washington University in St. Louis
- Elizabeth A. Regan
- Department of Medicine, Rheumatology, National Jewish Health
- Sefuiva M. Reupena
- Lutia i Puava ae Mapu i Fagalele
- Dan M. Roden
- Medicine, Pharmacology, and Biomedical Informatics, Clinical Pharmacology and Cardiovascular Medicine, Vanderbilt University Medical Center
- Jose Rodriguez-Santana
- Centro de Neumologia Pediatrica
- Colleen M. Sitlani
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Jennifer A. Smith
- Department of Epidemiology, School of Public Health, University of Michigan
- Hemant K. Tiwari
- Department of Biostatistics, University of Alabama at Birmingham School of Public Health
- Ramachandran S. Vasan
- Department of Medicine, School of Medicine, Boston University
- Zeyuan Wang
- Department of Epidemiology, Emory University Rollins School of Public Health
- Daniel E. Weeks
- Department of Human Genetics, School of Public Health, University of Pittsburgh
- Jennifer Wessel
- Department of Epidemiology, Indiana University
- Kerri L. Wiggins
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Lynne R. Wilkens
- Epidemiology Program, University of Hawaii Cancer Center
- Peter W. F. Wilson
- Atlanta VA Health Care System
- Lisa R. Yanek
- Department of Medicine, General Internal Medicine, Johns Hopkins University School of Medicine
- Zachary T. Yoneda
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center
- Wei Zhao
- Department of Epidemiology, School of Public Health, University of Michigan
- Sebastian Zöllner
- Department of Biostatistics, Department of Psychiatry, University of Michigan
- Donna K. Arnett
- Department of Epidemiology, Arnold School of Public Health, University of South Carolina
- Allison E. Ashley-Koch
- Duke Molecular Physiology Institute, Duke University Medical Center
- Kathleen C. Barnes
- Department of Medicine, University of Colorado School of Medicine
- John Blangero
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley
- Eric Boerwinkle
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- Esteban G. Burchard
- Bioengineering and Therapeutic Sciences and Medicine, Lung Biology Center, University of California, San Francisco
- April P. Carson
- Department of Medicine, University of Mississippi Medical Center
- Daniel I. Chasman
- Division of Preventive Medicine, Brigham and Women’s Hospital
- Yii-Der Ida Chen
- Department of Medical Genetics, Genomic Outcomes, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Joanne E. Curran
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley
- Myriam Fornage
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston
- Victor R. Gordeuk
- Department of Medicine, School of Medicine, University of Illinois at Chicago
- Jiang He
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University
- Susan R. Heckbert
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Lifang Hou
- Northwestern University
- Marguerite R. Irvin
- Department of Epidemiology, University of Alabama at Birmingham School of Public Health
- Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Center
- Ryan L. Minster
- Department of Human Genetics, School of Public Health, University of Pittsburgh
- Braxton D. Mitchell
- Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland
- Mehdi Nouraie
- Department of Medicine, School of Medicine, University of Pittsburgh
- Bruce M. Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington
- Laura M. Raffield
- Department of Genetics, University of North Carolina at Chapel Hill
- Alexander P. Reiner
- Department of Epidemiology, University of Washington
- Stephen S. Rich
- Center for Public Health Genomics, University of Virginia
- Jerome I. Rotter
- Department of Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- M. Benjamin Shoemaker
- Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center
- Nicholas L. Smith
- Department of Epidemiology, School of Public Health, University of Washington
- Kent D. Taylor
- Department of Pediatrics, Genomic Outcomes, The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
- Marilyn J. Telen
- Department of Medicine, Division of Hematology, Duke University School of Medical
- Scott T. Weiss
- Department of Medicine, Channing Division of Network Medicine, Harvard Medical School
- Yingze Zhang
- Department of Medicine, School of Medicine, University of Pittsburgh
- Nancy Heard-Costa
- Framingham Heart Study, School of Medicine, Boston University Chobanian & Avedisian School of Medicine
- Yan V. Sun
- Department of Epidemiology, Emory University Rollins School of Public Health
- Xihong Lin
- Department of Biostatistics, Harvard T.H. Chan School of Public Health
- L. Adrienne Cupples
- Department of Biostatistics, School of Public Health, Boston University
- Leslie A. Lange
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Anschutz Medical Campus
- Ching-Ti Liu
- Department of Biostatistics, School of Public Health, Boston University
- Ruth J. F. Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai
- Kari E. North
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill
- Anne E. Justice
- Population Health Sciences, Geisinger
- DOI
- https://doi.org/10.1038/s41467-025-58420-2
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 15
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.
