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Cited by 170Genetic Associations and EpidemiologyGenetics and Physical PerformanceGenetic Mapping and Diversity in Plants and Animals

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

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Huang, Jie, Huffman, Jennifer E., Huang, Yunfeng, Do Valle, Ítalo, Assimes, Themistocles L., Raghavan, Sridharan, Voight, Benjamin F., Liu, Chang +31 more·2022·Nature Communications
DOI 10.1038/s41467-022-35553-2PMC PMC9798356
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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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  • A discordant pQTL at rs35949016 was associated with lower CSF and higher plasma abundance of FUT8 (A allele) and with increased BMI.

    “We also detected a discordant pQTL at rs35949016 for lower CSF and higher plasma abundance of alpha-(1,6)-fucosyltransferase (FUT8, A allele; fig. S4D) that was associated with increased body mass index (BMI) (29).”

    From Low overlap of plasma and CSF protein quantitative trait loci affects protein discovery for neurological disease (2026) · cites this paper as [29]

    The Results section reports BMI-associated genetic variants generally, but the passages retrieved for rs35949016 and FUT8 do not identify this variant or link its A allele to increased BMI. They also do not address FUT8 abundance in CSF or plasma. The cited paper therefore does not verify the specific association attributed to it in our copy. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

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Sorted by citations

Authors
Huang, J., Huffman, J. E., Huang, Y., Do Valle, Í., Assimes, T. L., Raghavan, S., Voight, B. F., Liu, C., Barabási, A.-L., Huang, R. D. L., Hui, Q., Nguyen, X.-M. T., Ho, Y.-L., Djousse, L., Lynch, J. A., Vujkovic, M., Tcheandjieu, C., Tang, H., Damrauer, S. M., Reaven, P. D., Miller, D., Phillips, L. S., Ng, M. C. Y., Graff, M., Haiman, C. A., Loos, R. J. F., North, K. E., Yengo, L., Smith, G. D., Saleheen, D., Gaziano, J. M., Rader, D. J., Tsao, P. S., Cho, K., Chang, K.-M., Wilson, P. W. F., Program, V. M. V., Sun, Y. V., & O’Donnell, C. J.
Affiliations
  • Southern University of Science and Technology (CN)
  • VA Boston Healthcare System (US)
  • Emory University (US)
  • VA Palo Alto Health Care System (US)
  • VA Eastern Colorado Health Care System (US)
  • Philadelphia VA Medical Center (US)
  • University of Massachusetts Boston (US)
  • University of Arizona (US)
  • Center for Health Optimization and Implementation Research (US)
  • Vanderbilt University (US)
  • University of North Carolina at Chapel Hill (US)
  • University of Southern California (US)
  • University of Copenhagen (DK)
  • University of Bristol (GB)
  • Columbia University Irving Medical Center (US)
  • Brigham and Women's Hospital (US)
  • University of Pennsylvania (US)
Corresponding author
  • Sun, Yan V.
  • O’Donnell, Christopher J.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-12-29
Volume
13
Issue
1
Pages
7973-7973
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-35553-2
PMC
PMC9798356
OpenAlex
W4313442267
Cited by
170
References
9
Citations by year
2026: 40 · 2025: 56 · 2024: 54 · 2023: 19 · 2022: 1
FWCI
21.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • UA Campus Repository (The University of Arizona) (submittedVersion, cc-by)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Open Research (Auckland University of Technology) (submittedVersion, cc-by)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
  • Explore Bristol Research (submittedVersion, cc-by)
  • UNC Libraries
Funders
  • U.S. Department of Veterans Affairs (I01 BX003340, I01-CX001737, IK2-CX001780, IK2-CX001907, I01-BX004821, I01-BX003362, I01 BX005831, BX003362, BX004821)
  • Pfizer
  • Office of Research and Development
  • Dexcom
  • University of Bristol
  • Fonds National de la Recherche Luxembourg
  • Novo Nordisk
  • Novo Nordisk Fonden (NNF20OC0059313)
  • National Institutes of Health (190503, BX004821, DK101478)
  • Novartis Institutes for BioMedical Research
  • Medical Research Council (MC_UU_00011/1)
  • Australian Research Council (DE200100425)
  • National Heart, Lung, and Blood Institute (P01HL132825)
  • National Institute of Nursing Research (R01NR013520)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107786, R01DK101478, R01DK110113, UM1DK126194, R01DK075787)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
body mass index, obesity genetics, polygenic risk score, Mendelian randomization, phenotypic association, heart failure, ischemic heart disease, atrial fibrillation, chronic kidney disease, respiratory failure, asthma, musculoskeletal disorders, skin diseases, genetic architecture, novel loci, Million Veteran Program, African ancestry
MeSH terms
Phenomics, Humans, Obesity, Body Mass Index, Polymorphism, Single Nucleotide, Genomics, Genome-Wide Association Study, Mendelian Randomization Analysis

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