Genomics and phenomics of body mass index reveals a complex disease network
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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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 7973 |
| Tidsskrift | Nature Communications |
| Vol/bind | 13 |
| Udgave nummer | 1 |
| Antal sider | 10 |
| ISSN | 2041-1723 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
C.J.O’D. is employed by Novartis Institutes for Biomedical Research. P.D.R. has received research grant support from the following for-profit companies: Bristol Myers Squib, Lysulin Inc; and has consulted with Intercept Pharmaceuticals and Boston Heart Diagnostics. D.S. has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech, and Eli Lilly pharmaceuticals. L.S.P. declares that there is no duality of interest associated with this manuscript. With regard to potential conflicts of interest, L.S.P. has served on Scientific Advisory Boards for Boehringer Ingelheim and Janssen, and has or had research support from Merck, Pfizer, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline, and the Cystic Fibrosis Foundation. L.S.P. is also a cofounder and Officer and Board member and stockholder of a company, Diasyst, Inc., which markets software aimed to help improve diabetes management. S.M.D receives research support from Renalytix AI and Novo Nordisk to the University of Pennsylvania and consulting fees from Calico Labs. A.-L.B. is co-scientific founder of and is supported by Scipher Medicine, Inc. G.D.S. is a member of the Scientific Advisory Boards of Relation Therapeutics and Insitro. The remaining authors declare no competing interests.
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.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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