WHOLE GENOME SEQUENCING ANALYSIS OF BODY MASS INDEX IDENTIFIES NOVEL AFRICAN ANCESTRY-SPECIFIC RISK ALLELE
Authors: Zhang Xinruo , Brody Jennifer A. , Graff Mariaelisa , Highland Heather M. , Chami Nathalie , Xu Hanfei , Wang Zhe , Ferrier Kendra , Chittoor Geetha , Josyula Navya S. , 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 Margaret , 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 , Marchand Loic Le. , McDonald Merry-Lynn N. , McHugh Caitlin P. , Morrison Alanna C. , Naseri Take ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, 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. , Chen Yii-Der Ida , 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. , Shoemaker M. Benjamin , Smith Nicholas L. , Taylor Kent D. , Telen Marilyn J. , Weiss Scott T. , Zhang Yingze , Costa Nancy Heard- , Sun Yan V. , Lin Xihong , Cupples L. Adrienne , Lange Leslie A. , Liu Ching-Ti , Loos Ruth J.F. , North Kari E. , Justice Anne E. 
Published: August 2023

ABSTRACTObesity 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). Notably, we identified and replicated a novel low frequency single nucleotide polymorphism (SNP) inMTMR3that 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 thePOC5andDMDloci. 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.