Zhang Xinruo, Brody Jennifer A, Graff Mariaelisa, Highland Heather M, Chami Nathalie, Xu Hanfei, Wang Zhe, Ferrier Kendra R, Chittoor Geetha, Josyula Navya Shilpa, Meyer Mariah, Gupta Shreyash, Li Xihao, Li Zilin, Allison Matthew A, Becker Diane M, Bielak Lawrence F, Bis Joshua C, Boorgula Meher Preethi, Bowden Donald W, Broome Jai G, Buth Erin J, Carlson Christopher S, Chang Kyong-Mi, Chavan Sameer, Chiu Yen-Feng, Chuang Lee-Ming, Conomos Matthew P, DeMeo Dawn L, Du Mengmeng, Duggirala Ravindranath, Eng Celeste, Fohner Alison E, Freedman Barry I, Garrett Melanie E, Guo Xiuqing, Haiman Chris, Heavner Benjamin D, Hidalgo Bertha, Hixson James E, Ho Yuk-Lam, Hobbs Brian D, Hu Donglei, Hui Qin, Hwu Chii-Min, Jackson Rebecca D, Jain Deepti, Kalyani Rita R, Kardia Sharon L R, Kelly Tanika N, Lange Ethan M, LeNoir Michael, Li Changwei, Le Marchand Loic, McDonald Merry-Lynn N, McHugh Caitlin P, Morrison Alanna C, Naseri Take, O'Connell Jeffrey, O'Donnell Christopher J, Palmer Nicholette D, Pankow James S, Perry James A, Peters Ulrike, Preuss Michael H, Rao D C, Regan Elizabeth A, Reupena Sefuiva M, Roden Dan M, Rodriguez-Santana Jose, Sitlani Colleen M, Smith Jennifer A, Tiwari Hemant K, Vasan Ramachandran S, Wang Zeyuan, Weeks Daniel E, Wessel Jennifer, Wiggins Kerri L, Wilkens Lynne R, Wilson Peter W F, Yanek Lisa R, Yoneda Zachary T, Zhao Wei, Zöllner Sebastian, Arnett Donna K, Ashley-Koch Allison E, Barnes Kathleen C, Blangero John, Boerwinkle Eric, Burchard Esteban G, Carson April P, Chasman Daniel I, Ida Chen Yii-Der, Curran Joanne E, Fornage Myriam, Gordeuk Victor R, He Jiang, Heckbert Susan R, Hou Lifang, Irvin Marguerite R, Kooperberg Charles, Minster Ryan L, Mitchell Braxton D, Nouraie Mehdi, Psaty Bruce M, Raffield Laura M, Reiner Alexander P, Rich Stephen S, Rotter Jerome I, Benjamin Shoemaker M, Smith Nicholas L, Taylor Kent D, Telen Marilyn J, Weiss Scott T, Zhang Yingze, Heard-Costa Nancy, Sun Yan V, Lin Xihong, Cupples L Adrienne, Lange Leslie A, Liu Ching-Ti, Loos Ruth J F, North Kari E, Justice Anne E
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Nat Commun. 2025 Apr 11;16(1):3470. doi: 10.1038/s41467-025-58420-2.
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), 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.
肥胖是一种与高死亡率相关的重大公共卫生危机。以往研究体重指数（BMI）的全基因组关联研究（GWAS）在很大程度上依赖于来自欧洲个体的推测数据。本研究利用了精准医学全基因组学（TOPMed）项目中88873名参与者的全基因组测序（WGS）数据，其中51%为非欧洲人群体。我们发现了18个与BMI相关的信号（P < 5×10），包括两个次要信号。值得注意的是，我们在MTMR3中鉴定并重复了一个新的低频单核苷酸多态性（SNP），该多态性在非洲裔个体中很常见。通过多样化的研究人群，我们在已知的BMI基因座中进一步鉴定出两个新的次要信号，并在POC5和DMD基因座中确定了两个可能的因果变异。我们的工作证明了结合WGS和多样化队列在扩展当前肥胖风险变异和基因目录方面的益处，使我们离个性化医疗又近了一步。
