Genomics and phenomics of body mass index reveals a complex disease network

• Type of Material: Article
• Authors: Jie Huang, Southern University of Science & Technology; Jennifer E. Huffman, VA Boston Healthcare System; Yunfeng Huang, Emory University; Italo Do Valle, Northeastern University; Themistocles L. Assimes, VA Palo Alto Health Care System; Sridharan Raghavan, VA Eastern Colorado Healthcare System; Lawrence Phillips, Emory University; Peter Wilson, Emory University; Yan Sun, Emory University; Christopher J. O'Donnell, VA Boston Healthcare System
• Language: English
• Date: 2022-12-29
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-35553-2
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 7973
• End Page: 7973
• Grant/Funding Information: This research is supported by funding from the Department of Veterans Affairs Office of Research and Development, Million Veteran Program Grant I01-BX003340 and I01-BX004821 (PIs: P.W.F.W and K.C.) and I01-BX003362 (PIs: P.S.T. and K.C.). Y.H. and Y.V.S. are supported in part by R01 NR013520. B.V. is supported in part by R01 DK101478 and DK126194. S.M.D. is supported in part by IK2-CX001780. Ruth JF Loos is supported by finding from the NIH (R01DK110113, R01DK075787, R01DK107786), the Novo Nordisk Foundation (190503), and the Danish National Research Fund. L.Y. is supported by the Australian Research Council (DE200100425). A-L.B. is supported in part by the Department of Veterans Affairs Contract #36C24122N0769, NIH grant #1P01HL132825, and European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 810115 – DYNASNET. G.D.S. works within the MRC Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). P.D.R. has received research grant support from Dexcom, Inc. This publication does not represent the views of the Department of Veterans Affairs or the United States Government. A list of MVP investigators can be found in Supplementary Materials.
• Keywords: METAANALYSIS; ASSOCIATION; Science & Technology - Other Topics; Multidisciplinary Sciences; HEALTH; UK BIOBANK; BARIATRIC SURGERY; Science & Technology; OBESITY
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.