. 2025 Apr 11;16(1):3470.

doi: 10.1038/s41467-025-58420-2.

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

Xinruo Zhang^#¹, Jennifer A Brody^#², Mariaelisa Graff^#³, Heather M Highland^#³, Nathalie Chami^#^{4

5}, Hanfei Xu⁶, Zhe Wang⁴, Kendra R Ferrier⁷, Geetha Chittoor⁸, Navya Shilpa Josyula⁸, Mariah Meyer⁷, Shreyash Gupta⁸, Xihao Li^{9

10

11}, Zilin Li^{12

13}, Matthew A Allison¹⁴, Diane M Becker¹⁵, Lawrence F Bielak¹⁶, Joshua C Bis², Meher Preethi Boorgula¹⁷, Donald W Bowden¹⁸, Jai G Broome^{19

20}, Erin J Buth¹⁹, Christopher S Carlson²¹, Kyong-Mi Chang^{22

23}, Sameer Chavan¹⁷, Yen-Feng Chiu²⁴, Lee-Ming Chuang²⁵, Matthew P Conomos¹⁹, Dawn L DeMeo²⁶, Mengmeng Du²⁷, Ravindranath Duggirala^{28

29}, Celeste Eng³⁰, Alison E Fohner³¹, Barry I Freedman³², Melanie E Garrett³³, Xiuqing Guo³⁴, Chris Haiman³⁵, Benjamin D Heavner¹⁹, Bertha Hidalgo³⁶, James E Hixson³⁷, Yuk-Lam Ho³⁸, Brian D Hobbs^{26

39}, Donglei Hu³⁰, Qin Hui^{40

41}, Chii-Min Hwu⁴², Rebecca D Jackson⁴³, Deepti Jain¹⁹, Rita R Kalyani⁴⁴, Sharon L R Kardia¹⁶, Tanika N Kelly⁴⁵, Ethan M Lange⁷, Michael LeNoir⁴⁶, Changwei Li⁴⁵, Loic Le Marchand⁴⁷, Merry-Lynn N McDonald⁴⁸, Caitlin P McHugh¹⁹, Alanna C Morrison⁴⁹, Take Naseri^{50

51}; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Jeffrey O'Connell⁵², Christopher J O'Donnell^{38

53}, Nicholette D Palmer¹⁸, James S Pankow⁵⁴, James A Perry⁵⁵, Ulrike Peters²¹, Michael H Preuss⁴, D C Rao⁵⁶, Elizabeth A Regan⁵⁷, Sefuiva M Reupena⁵⁸, Dan M Roden⁵⁹, Jose Rodriguez-Santana⁶⁰, Colleen M Sitlani², Jennifer A Smith^{16

61}, Hemant K Tiwari⁶², Ramachandran S Vasan⁶³, Zeyuan Wang⁴⁰, Daniel E Weeks^{64

65}, Jennifer Wessel^{66

67

68}, Kerri L Wiggins², Lynne R Wilkens⁴⁷, Peter W F Wilson^{41

69}, Lisa R Yanek¹⁵, Zachary T Yoneda⁷⁰, Wei Zhao^{16

61}, Sebastian Zöllner⁷¹, Donna K Arnett⁷², Allison E Ashley-Koch³³, Kathleen C Barnes¹⁷, John Blangero⁷³, Eric Boerwinkle⁴⁹, Esteban G Burchard⁷⁴, April P Carson⁷⁵, Daniel I Chasman^{76

77}, Yii-Der Ida Chen⁷⁸, Joanne E Curran⁷³, Myriam Fornage^{49

79}, Victor R Gordeuk⁸⁰, Jiang He⁴⁵, Susan R Heckbert^{2

81}, Lifang Hou⁸², Marguerite R Irvin⁸³, Charles Kooperberg²¹, Ryan L Minster⁶⁴, Braxton D Mitchell⁸⁴, Mehdi Nouraie⁸⁵, Bruce M Psaty^{2

81

86}, Laura M Raffield⁸⁷, Alexander P Reiner⁸¹, Stephen S Rich⁸⁸, Jerome I Rotter³⁴, M Benjamin Shoemaker⁷⁰, Nicholas L Smith^{89

90

91}, Kent D Taylor³⁴, Marilyn J Telen⁹², Scott T Weiss⁹³, Yingze Zhang⁸⁵, Nancy Heard-Costa⁹⁴, Yan V Sun^{40

41}, Xihong Lin^{9

95}, L Adrienne Cupples⁶, Leslie A Lange⁷, Ching-Ti Liu⁶, Ruth J F Loos^{4

5

96}, Kari E North³, Anne E Justice⁹⁷

Collaborators, Affiliations

Collaborators

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium:
Loic Le Marchand, Yii-Der Ida Chen, M Benjamin Shoemaker

Affiliations

¹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. xinruo@email.unc.edu.
² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
⁷ Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
⁸ Population Health Sciences, Geisinger, Danville, PA, USA.
⁹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ School of Mathematics and Statistics and KLAS, Northeast Normal University, Changchun, Jilin, China.
¹⁴ Department of Family Medicine, Division of Preventive Medicine, The University of California San Diego, La Jolla, CA, USA.
¹⁵ Department of Medicine, General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁸ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁹ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
²⁰ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.
²¹ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²² The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
²³ University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁴ Institute of Population Health Sciences, National Health Research Institutes, Taipei, Taiwan.
²⁵ Department of Internal Medicine, Division of Metabolism/Endocrinology, National Taiwan University Hospital, Taipei, Taiwan.
²⁶ Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁷ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁸ Life Sciences, College of Arts and Sciences, Texas A&M University-San Antonio, San Antonio, TX, USA.
²⁹ Department of Health and Behavioral Sciences, College of Arts and Sciences, Texas A&M University-San Antonio, San Antonio, TX, USA.
³⁰ Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
³¹ Epidemiology, Institute of Public Health Genetics, School of Public Health, University of Washington, Seattle, WA, USA.
³² Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
³⁴ 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, Torrance, CA, USA.
³⁵ Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
³⁷ Department of Epidemiology, School of Public Health, UTHealth Houston, Houston, TX, USA.
³⁸ Veterans Affairs Boston Healthcare System, Boston, MA, USA.
³⁹ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁰ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
⁴¹ Atlanta VA Health Care System, Decatur, GA, USA.
⁴² Department of Medicine, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan, Taiwan.
⁴³ Endocrinology, Ohio State University, Columbus, OH, USA.
⁴⁴ Department of Medicine, Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁵ Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
⁴⁶ Department of Pediatrics, Bay Area Pediatrics, Oakland, CA, USA.
⁴⁷ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁴⁸ Department of Medicine, Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴⁹ Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁰ Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
⁵¹ International Health Institute, Brown University, Providence, RI, USA.
⁵² Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, MD, USA.
⁵³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁴ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
⁵⁵ Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA.
⁵⁶ Center for Biostatistics and Data Science, Washington University in St. Louis, St. Louis, MO, USA.
⁵⁷ Department of Medicine, Rheumatology, National Jewish Health, Denver, CO, USA.
⁵⁸ Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.
⁵⁹ Medicine, Pharmacology, and Biomedical Informatics, Clinical Pharmacology and Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶⁰ Centro de Neumologia Pediatrica, San Juan, PR, USA.
⁶¹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁶² Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
⁶³ Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
⁶⁴ Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁵ Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁶ Department of Epidemiology, Indiana University, Indianapolis, IN, USA.
⁶⁷ Department of Medicine, Indiana University, Indianapolis, IN, USA.
⁶⁸ Diabaetes Translational Research Center, Indiana University, Indianapolis, IN, USA.
⁶⁹ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁷⁰ Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷¹ Department of Biostatistics, Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
⁷² Department of Epidemiology, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
⁷³ Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA.
⁷⁴ Bioengineering and Therapeutic Sciences and Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
⁷⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁷⁶ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁷ Harvard Medical School, Boston, MA, USA.
⁷⁸ Department of Medical Genetics, Genomic Outcomes, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷⁹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸⁰ Department of Medicine, School of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
⁸¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁸² Northwestern University, Chicago, IL, USA.
⁸³ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
⁸⁴ Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD, USA.
⁸⁵ Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁸⁶ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁸⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁸⁹ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
⁹⁰ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.
⁹¹ Seattle Epidemiologic Research and Information Center, Office of Research and Development, Department of Veterans Affairs, Seattle, WA, USA.
⁹² Department of Medicine, Division of Hematology, Duke University School of Medical, Durham, NC, USA.
⁹³ Department of Medicine, Channing Division of Network Medicine, Harvard Medical School, Boston, MA, USA.
⁹⁴ Framingham Heart Study, School of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁹⁵ Department of Statistics, Harvard University, Cambridge, MA, USA.
⁹⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹⁷ Population Health Sciences, Geisinger, Danville, PA, USA. aejustice1@geisinger.edu.

^# Contributed equally.

PMID: 40216759
PMCID: PMC11992084
DOI: 10.1038/s41467-025-58420-2

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

Xinruo Zhang et al. Nat Commun. 2025.

. 2025 Apr 11;16(1):3470.

doi: 10.1038/s41467-025-58420-2.

Authors

Collaborators

NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium:
Loic Le Marchand, Yii-Der Ida Chen, M Benjamin Shoemaker

Affiliations

¹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. xinruo@email.unc.edu.
² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
³ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶ Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.
⁷ Division of Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
⁸ Population Health Sciences, Geisinger, Danville, PA, USA.
⁹ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁰ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹¹ Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA.
¹³ School of Mathematics and Statistics and KLAS, Northeast Normal University, Changchun, Jilin, China.
¹⁴ Department of Family Medicine, Division of Preventive Medicine, The University of California San Diego, La Jolla, CA, USA.
¹⁵ Department of Medicine, General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁶ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
¹⁷ Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁸ Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹⁹ Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
²⁰ Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, USA.
²¹ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
²² The Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
²³ University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁴ Institute of Population Health Sciences, National Health Research Institutes, Taipei, Taiwan.
²⁵ Department of Internal Medicine, Division of Metabolism/Endocrinology, National Taiwan University Hospital, Taipei, Taiwan.
²⁶ Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁷ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁸ Life Sciences, College of Arts and Sciences, Texas A&M University-San Antonio, San Antonio, TX, USA.
²⁹ Department of Health and Behavioral Sciences, College of Arts and Sciences, Texas A&M University-San Antonio, San Antonio, TX, USA.
³⁰ Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
³¹ Epidemiology, Institute of Public Health Genetics, School of Public Health, University of Washington, Seattle, WA, USA.
³² Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
³⁴ 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, Torrance, CA, USA.
³⁵ Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³⁶ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
³⁷ Department of Epidemiology, School of Public Health, UTHealth Houston, Houston, TX, USA.
³⁸ Veterans Affairs Boston Healthcare System, Boston, MA, USA.
³⁹ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁰ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
⁴¹ Atlanta VA Health Care System, Decatur, GA, USA.
⁴² Department of Medicine, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital, Taipei, Taiwan, Taiwan.
⁴³ Endocrinology, Ohio State University, Columbus, OH, USA.
⁴⁴ Department of Medicine, Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴⁵ Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA.
⁴⁶ Department of Pediatrics, Bay Area Pediatrics, Oakland, CA, USA.
⁴⁷ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁴⁸ Department of Medicine, Pulmonary, Allergy and Critical Care, University of Alabama at Birmingham, Birmingham, AL, USA.
⁴⁹ Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁰ Naseri & Associates Public Health Consultancy Firm and Family Health Clinic, Apia, Samoa.
⁵¹ International Health Institute, Brown University, Providence, RI, USA.
⁵² Department of Medicine, Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, MD, USA.
⁵³ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁴ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
⁵⁵ Department of Medicine, School of Medicine, University of Maryland, Baltimore, MD, USA.
⁵⁶ Center for Biostatistics and Data Science, Washington University in St. Louis, St. Louis, MO, USA.
⁵⁷ Department of Medicine, Rheumatology, National Jewish Health, Denver, CO, USA.
⁵⁸ Lutia i Puava ae Mapu i Fagalele, Apia, Samoa.
⁵⁹ Medicine, Pharmacology, and Biomedical Informatics, Clinical Pharmacology and Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶⁰ Centro de Neumologia Pediatrica, San Juan, PR, USA.
⁶¹ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
⁶² Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
⁶³ Department of Medicine, School of Medicine, Boston University, Boston, MA, USA.
⁶⁴ Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁵ Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
⁶⁶ Department of Epidemiology, Indiana University, Indianapolis, IN, USA.
⁶⁷ Department of Medicine, Indiana University, Indianapolis, IN, USA.
⁶⁸ Diabaetes Translational Research Center, Indiana University, Indianapolis, IN, USA.
⁶⁹ Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
⁷⁰ Department of Medicine, Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷¹ Department of Biostatistics, Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA.
⁷² Department of Epidemiology, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
⁷³ Department of Human Genetics and South Texas Diabetes and Obesity Institute, School of Medicine, University of Texas Rio Grande Valley, Brownsville, TX, USA.
⁷⁴ Bioengineering and Therapeutic Sciences and Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, CA, USA.
⁷⁵ Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁷⁶ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁷⁷ Harvard Medical School, Boston, MA, USA.
⁷⁸ Department of Medical Genetics, Genomic Outcomes, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷⁹ Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁸⁰ Department of Medicine, School of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
⁸¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁸² Northwestern University, Chicago, IL, USA.
⁸³ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
⁸⁴ Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD, USA.
⁸⁵ Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁸⁶ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
⁸⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁸⁹ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
⁹⁰ Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA.
⁹¹ Seattle Epidemiologic Research and Information Center, Office of Research and Development, Department of Veterans Affairs, Seattle, WA, USA.
⁹² Department of Medicine, Division of Hematology, Duke University School of Medical, Durham, NC, USA.
⁹³ Department of Medicine, Channing Division of Network Medicine, Harvard Medical School, Boston, MA, USA.
⁹⁴ Framingham Heart Study, School of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
⁹⁵ Department of Statistics, Harvard University, Cambridge, MA, USA.
⁹⁶ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹⁷ Population Health Sciences, Geisinger, Danville, PA, USA. aejustice1@geisinger.edu.

^# Contributed equally.

PMID: 40216759
PMCID: PMC11992084
DOI: 10.1038/s41467-025-58420-2

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.

PubMed Disclaimer

Conflict of interest statement

Competing interests: B.D.Ho. receives grant support from Bayer and has received an honorarium from AstraZeneca for an educational lecture. B.M.Ps. serve on the TOPMed Steering Committee. C.J.O. is employed by Novartis Institute of Biomedical Research, Cambridge, MA. D.L.D. received grants from Bayer and honoraria from Novartis. K.C.B. is an employee of Tempus. L.M.R. and S.S.R. are consultants for the TOPMed Administrative Coordinating Center (through Westat). U.P. was a consultant with AbbVie, and her husband is holding individual stocks for the following companies: BioNTech SE – ADR, Amazon, CureVac BV, NanoString Technologies, Google/Alphabet Inc Class C, NVIDIA Corp, Microsoft Corp. XLin is a consultant of AbbVie Pharmaceuticals and Verily Life Sciences. The remaining authors declare no competing interests.

Figures

**Fig. 1. Study population group composition.**
A Pairwise scatter plots of the first three principal components (PCs) by population group. B The number and proportion of participants by population group. Our study population was composed of 88,873 participants from 15 population groups, 51% of which are non-European.

**Fig. 2. Summary of significant association findings.**
A Manhattan plot of multi-population, single-variant analysis (N = 88,873 individuals). The novel locus *(MTMR3)* is highlighted in red. Previously reported BMI loci are in dark beige. The horizontal dashed line indicates the genome-wide significance threshold two-sided P = 5 × 10⁻⁹, to account for multiple testing. B Scatterplot showing the minor allele frequency compared to the absolute value of the estimated effect of the index variant at each significant locus. All effect estimates are from the primary analysis conducted across all population groups. Previously reported loci are highlighted in blue, while the novel locus is in red; circles represent the most significant variant at each locus, and triangles show newly reported secondary signals within known loci.

**Fig. 3. Forest plot of rs111490516 replication.**
The forest plot, centered on effect estimates with 95% confidence intervals, is oriented on the BMI-increasing allele. Effect estimates are provided as standard deviation in BMI per allele. Standard errors and P-values of the effect estimates are provided in Supplementary Data 8.

See this image and copyright information in PMC

Update of

WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE.
Zhang X, Brody JA, Graff M, Highland HM, Chami N, Xu H, Wang Z, Ferrier K, Chittoor G, Josyula NS, Li X, Li Z, Allison MA, Becker DM, Bielak LF, Bis JC, Boorgula MP, Bowden DW, Broome JG, Buth EJ, Carlson CS, Chang KM, Chavan S, Chiu YF, Chuang LM, Conomos MP, DeMeo DL, Du M, Duggirala R, Eng C, Fohner AE, Freedman BI, Garrett ME, Guo X, Haiman C, Heavner BD, Hidalgo B, Hixson JE, Ho YL, Hobbs BD, Hu D, Hui Q, Hwu CM, Jackson RD, Jain D, Kalyani RR, Kardia SLR, Kelly TN, Lange EM, LeNoir M, Li C, Marchand LL, McDonald MN, McHugh CP, Morrison AC, Naseri T; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; O'Connell J, O'Donnell CJ, Palmer ND, Pankow JS, Perry JA, Peters U, Preuss MH, Rao DC, Regan EA, Reupena SM, Roden DM, Rodriguez-Santana J, Sitlani CM, Smith JA, Tiwari HK, Vasan RS, Wang Z, Weeks DE, Wessel J, Wiggins KL, Wilkens LR, Wilson PWF, Yanek LR, Yoneda ZT, Zhao W, Zöllner S, Arnett DK, Ashley-Koch AE, Barnes KC, Blangero J, Boerwinkle E, Burchard EG, Carson AP, Chasman DI, Chen YI, Curran JE, Fornage M, Gordeuk VR, He J, Heckbert SR, Hou L, Irvin MR, Kooperberg C, Minster RL, Mitchell BD, Nouraie M, Psaty BM, Raffield LM, Reiner AP, Rich SS, Rotter JI, Shoe… See abstract for full author list ➔ Zhang X, et al. medRxiv [Preprint]. 2023 Aug 22:2023.08.21.23293271. doi: 10.1101/2023.08.21.23293271. medRxiv. 2023. Update in: Nat Commun. 2025 Apr 11;16(1):3470. doi: 10.1038/s41467-025-58420-2. PMID: 37662265 Free PMC article. Updated. Preprint.

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

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

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