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

doi:10.1038/s41467-022-35553-2

. 2022 Dec 29;13(1):7973.

doi: 10.1038/s41467-022-35553-2.

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

Jie Huang^#¹, Jennifer E Huffman^#², Yunfeng Huang^#^{3

4}, Ítalo Do Valle^{5

6}, Themistocles L Assimes^{7

8}, Sridharan Raghavan^{9

10}, Benjamin F Voight^{11

12

13

14}, Chang Liu³, Albert-László Barabási^{5

15

16}, Rose D L Huang², Qin Hui^{3

4}, Xuan-Mai T Nguyen^{17

18}, Yuk-Lam Ho¹⁸, Luc Djousse^{18

19}, Julie A Lynch^{20

21}, Marijana Vujkovic^{11

22}, Catherine Tcheandjieu^{7

8}, Hua Tang^{7

23}, Scott M Damrauer^{11

24

25}, Peter D Reaven^{26

27}, Donald Miller²⁸, Lawrence S Phillips^{4

29}, Maggie C Y Ng³⁰, Mariaelisa Graff³¹, Christopher A Haiman³², Ruth J F Loos^{33

34

35}, Kari E North³¹, Loic Yengo³⁶, George Davey Smith^{37

38}, Danish Saleheen^{39

40

41}, J Michael Gaziano^{18

19}, Daniel J Rader^{22

25}, Philip S Tsao^{7

8}, Kelly Cho^{18

19}, Kyong-Mi Chang^{11

22}, Peter W F Wilson^{3

4

42}; VA Million Veteran Program; Yan V Sun^{43

44}, Christopher J O'Donnell^{45

46

47}

Affiliations

¹ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
² Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
³ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
⁴ Atlanta VA Health Care System, Decatur, GA, USA.
⁵ Network Science Institute and Department of Physics, Northeastern University, Boston, MA, USA.
⁶ Division of Population Health and Data Science, MAVERIC, VA Boston Healthcare System, Boston, MA, USA.
⁷ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ VA Eastern Colorado Healthcare System, Aurora, CO, USA.
¹⁰ University of Colorado School of Medicine, Aurora, CO, USA.
¹¹ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
¹² Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Institute of Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Network and Data Science, Central European University, Budapest, Hungary.
¹⁷ Carle Illinois College of Medicine, Champaign, IL, USA.
¹⁸ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
¹⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ VA Salt Lake City Healthcare, Salt Lake City, UT, USA.
²¹ University of Massachusetts, Boston, MA, USA.
²² Department of Medicine; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
²⁴ Department of Surgery; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁶ Phoenix VA Health Care System, Phoenix, AZ, USA.
²⁷ College of Medicine, University of Arizona, Phoenix, AZ, USA.
²⁸ Center for Healthcare Organization and Implementation Research, Bedford VA Medical Center, Bedford, MA, USA.
²⁹ Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
³⁰ Vanderbilt Genetics Institute and Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
³² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁴ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³⁶ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
³⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³⁸ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
³⁹ Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
⁴⁰ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁴¹ Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
⁴² Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
⁴³ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA. yan.v.sun@emory.edu.
⁴⁴ Atlanta VA Health Care System, Decatur, GA, USA. yan.v.sun@emory.edu.
⁴⁵ Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA. christopher.odonnell@va.gov.
⁴⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. christopher.odonnell@va.gov.
⁴⁷ Cardiology Section, VA Boston Healthcare System, Boston, MA, USA. christopher.odonnell@va.gov.

^# Contributed equally.

PMID: 36581621
PMCID: PMC9798356
DOI: 10.1038/s41467-022-35553-2

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

Jie Huang et al. Nat Commun. 2022.

. 2022 Dec 29;13(1):7973.

doi: 10.1038/s41467-022-35553-2.

Authors

Affiliations

¹ School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen, Guangdong, China.
² Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
³ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
⁴ Atlanta VA Health Care System, Decatur, GA, USA.
⁵ Network Science Institute and Department of Physics, Northeastern University, Boston, MA, USA.
⁶ Division of Population Health and Data Science, MAVERIC, VA Boston Healthcare System, Boston, MA, USA.
⁷ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ VA Eastern Colorado Healthcare System, Aurora, CO, USA.
¹⁰ University of Colorado School of Medicine, Aurora, CO, USA.
¹¹ Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
¹² Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Institute of Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
¹⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Network and Data Science, Central European University, Budapest, Hungary.
¹⁷ Carle Illinois College of Medicine, Champaign, IL, USA.
¹⁸ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
¹⁹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁰ VA Salt Lake City Healthcare, Salt Lake City, UT, USA.
²¹ University of Massachusetts, Boston, MA, USA.
²² Department of Medicine; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²³ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
²⁴ Department of Surgery; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁵ Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
²⁶ Phoenix VA Health Care System, Phoenix, AZ, USA.
²⁷ College of Medicine, University of Arizona, Phoenix, AZ, USA.
²⁸ Center for Healthcare Organization and Implementation Research, Bedford VA Medical Center, Bedford, MA, USA.
²⁹ Division of Endocrinology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
³⁰ Vanderbilt Genetics Institute and Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
³² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁴ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁵ Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
³⁶ Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
³⁷ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³⁸ Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
³⁹ Center for Non-Communicable Diseases, Karachi, Sindh, Pakistan.
⁴⁰ Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
⁴¹ Department of Cardiology, Columbia University Irving Medical Center, New York, NY, USA.
⁴² Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
⁴³ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA. yan.v.sun@emory.edu.
⁴⁴ Atlanta VA Health Care System, Decatur, GA, USA. yan.v.sun@emory.edu.
⁴⁵ Center for Population Genomics, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA. christopher.odonnell@va.gov.
⁴⁶ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. christopher.odonnell@va.gov.
⁴⁷ Cardiology Section, VA Boston Healthcare System, Boston, MA, USA. christopher.odonnell@va.gov.

^# Contributed equally.

PMID: 36581621
PMCID: PMC9798356
DOI: 10.1038/s41467-022-35553-2

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.

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Conflict of interest statement

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.

Figures

**Fig. 1. Summary of phenome-wide Mendelian randomization analysis using GRS_BMI.**
Red dots represent a statistically significant positive association with GRS_BMI ( ↑ GRS_BMI = ↑ disease risk), and black dots represent a statistically significant negative association in the MR analysis after multiple testing correction (two-sided test with nominal p-value less than 4.02 × 10⁻⁵). Top 100 associations with lowest p-values in the MR analysis are labeled including 98 positive associations (colored font) and two negative associations (black font) from 13 systems. Abbreviations (clockwise): Circulatory: circulatory system; Co: congenital anomalies; Derm: dermatologic; Endo/Metab: endocrine/metabolic; Hema: hematopoietic; Infect: infectious diseases; Injuries: injuries & poisonings; Mental: mental disorders; Neuro: neurological; Respir: respiratory; Sym: symptoms.

**Fig. 2. Phenotypic network map.**
Nodes represent phecodes at the three-digit level and the links represent significant disease-disease associations (ϕ-correlation). Node size is proportional to network connectivity (degree). Individual disease communities (A-G) are described in the Supplementary Materials.

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References

1. Collaborators, G.B.D.O. et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N. Engl. J. Med. 2017;377:13–27. doi: 10.1056/NEJMoa1614362. - DOI - PMC - PubMed
1. Ogden, C.L. et al. Trends in Obesity Prevalence by Race and Hispanic Origin-1999-2000 to 2017-2018. JAMA (2020). - PMC - PubMed
1. Carlsson LMS, et al. Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study. N. Engl. J. Med. 2020;383:1535–1543. doi: 10.1056/NEJMoa2002449. - DOI - PMC - PubMed
1. Reges O, et al. Association of Bariatric Surgery Using Laparoscopic Banding, Roux-en-Y Gastric Bypass, or Laparoscopic Sleeve Gastrectomy vs Usual Care Obesity Management With All-Cause Mortality. JAMA. 2018;319:279–290. doi: 10.1001/jama.2017.20513. - DOI - PMC - PubMed
1. Syn NL, et al. Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants. Lancet. 2021;397:1830–1841. doi: 10.1016/S0140-6736(21)00591-2. - DOI - PubMed

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[1] Collaborators, G.B.D.O. et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N. Engl. J. Med. 2017;377:13–27. doi: 10.1056/NEJMoa1614362. - DOI - PMC - PubMed

[2] Collaborators, G.B.D.O. et al. Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N. Engl. J. Med. 2017;377:13–27. doi: 10.1056/NEJMoa1614362. - DOI - PMC - PubMed

[3] Ogden, C.L. et al. Trends in Obesity Prevalence by Race and Hispanic Origin-1999-2000 to 2017-2018. JAMA (2020). - PMC - PubMed

[4] Ogden, C.L. et al. Trends in Obesity Prevalence by Race and Hispanic Origin-1999-2000 to 2017-2018. JAMA (2020). - PMC - PubMed

[5] Carlsson LMS, et al. Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study. N. Engl. J. Med. 2020;383:1535–1543. doi: 10.1056/NEJMoa2002449. - DOI - PMC - PubMed

[6] Carlsson LMS, et al. Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study. N. Engl. J. Med. 2020;383:1535–1543. doi: 10.1056/NEJMoa2002449. - DOI - PMC - PubMed

[7] Reges O, et al. Association of Bariatric Surgery Using Laparoscopic Banding, Roux-en-Y Gastric Bypass, or Laparoscopic Sleeve Gastrectomy vs Usual Care Obesity Management With All-Cause Mortality. JAMA. 2018;319:279–290. doi: 10.1001/jama.2017.20513. - DOI - PMC - PubMed

[8] Reges O, et al. Association of Bariatric Surgery Using Laparoscopic Banding, Roux-en-Y Gastric Bypass, or Laparoscopic Sleeve Gastrectomy vs Usual Care Obesity Management With All-Cause Mortality. JAMA. 2018;319:279–290. doi: 10.1001/jama.2017.20513. - DOI - PMC - PubMed

[9] Syn NL, et al. Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants. Lancet. 2021;397:1830–1841. doi: 10.1016/S0140-6736(21)00591-2. - DOI - PubMed

[10] Syn NL, et al. Association of metabolic-bariatric surgery with long-term survival in adults with and without diabetes: a one-stage meta-analysis of matched cohort and prospective controlled studies with 174 772 participants. Lancet. 2021;397:1830–1841. doi: 10.1016/S0140-6736(21)00591-2. - DOI - PubMed

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

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

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