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

DOI
https://doi.org/10.1038/s41467-025-58420-2
Journal volume & issue
Vol. 16, no. 1
pp. 1 – 15

Abstract

Read online

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.