Genome-wide association study provides novel insight into the genetic architecture of severe obesity

Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95th percentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥ 40 kg/m2 and Obesity Class IV BMI ≥ 50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated three novel signals in known loci of BMI [TENM2, PLCL2, ZNF184], associated with SevO traits. We confirmed a large overlap in the genetic architecture of continuous BMI and severe obesity phenotypes, suggesting little genetic heterogeneity in common variants, between obesity subgroups. Systematic analyses combining functional mapping, polygenic risk scores (PRS), phenome wide association studies (PheWAS) and environmental risk factors further reinforce shared downstream comorbidities associated with continuous measures of BMI and the importance of known lifestyle factors in interaction with genetic predisposition to SevO. Our study expands the number of SevO signals, demonstrates a strong overlap in the genetic architecture of SevO and BMI and reveals a remarkable impact of SevO on the clinical phenome, affording new opportunities for clinical prevention and mechanistic insights.

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Publication Details

Journal
PLoS Genetics
Published
2025-09-12
DOI
https://doi.org/10.1371/journal.pgen.1011842
Citations
3
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
5.45

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article

Genome-wide association study provides novel insight into the genetic architecture of severe obesity

Charles Kooperberg, Mariah Meyer, Ryan W. Walker, Esteban J. Parra et al.
3 citations
PLoS Genetics
Genetic Associations and Epidemiology
5.45
article

Genome-wide association study provides novel insight into the genetic architecture of severe obesity

Charles Kooperberg, Mariah Meyer, Ryan W. Walker, Esteban J. Parra, Ruth J. F. Loos, Qin Hui, Steven Buyske, Kendra Ferrier, Susan P. Fisher‐Hoch, Penny Gordon‐Larsen, Alyssa Scartozzi, Geetha Chittoor, Genevieve L. Wojcik, Gregorio V. Linchangco, Peter W F Wilson, Luc Djoussé, Yan V. Sun, Jennifer E Below, Kristin L. Young, Sharon L. R. Kardia, Laura M. Raffield, Michael H Preuss, Christopher Haiman, Eimear E. Kenny, Kelly Cho, Baiyu Qi, Mariaelisa Graff, Joseph B. McCormick, Nathalie Chami, Michael Gaziano, Ulrike Peters, Navya Shilpa Josyula, Roelof A. J. Smit, Ethan M. Lange, David R. Weir, Mohanraj Krishnan, Jennifer A. Smith, Anne E. Justice, Miguel Cruz, Mohammad Yaser Anwar, Lisa R. Yanek, Stephen S. Rich, Iona C. Cheng, Miryoung Lee, Dhananjay Vaidya, Chr. Bauer, Lawrence F. Bielak, Wei Zhao, Jessica D. Faul, Ching‐Ti Liu, Hung‐Hsin Chen, Christopher R. Gignoux, Heather M. Highland, Frida Lona‐Durazo, Rashedeh Roshani, Xiaoyu Zhang, Myriam Fornage, Shuwei Liu, Leslie A. Lange, Yujie Wang, Renée de Mutsert, Kari E North, R. Dickerson, Jesús Peralta, Benjamin S Hadad, Jamie Gomez-Zamudio
article en
3 citations

Abstract

Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95th percentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥ 40 kg/m2 and Obesity Class IV BMI ≥ 50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated three novel signals in known loci of BMI [TENM2, PLCL2, ZNF184], associated with SevO traits. We confirmed a large overlap in the genetic architecture of continuous BMI and severe obesity phenotypes, suggesting little genetic heterogeneity in common variants, between obesity subgroups. Systematic analyses combining functional mapping, polygenic risk scores (PRS), phenome wide association studies (PheWAS) and environmental risk factors further reinforce shared downstream comorbidities associated with continuous measures of BMI and the importance of known lifestyle factors in interaction with genetic predisposition to SevO. Our study expands the number of SevO signals, demonstrates a strong overlap in the genetic architecture of SevO and BMI and reveals a remarkable impact of SevO on the clinical phenome, affording new opportunities for clinical prevention and mechanistic insights.

PLoS GeneticsVol. 21(9)
Rutgers, The State University of New Jersey (US), Boston University (US), University of North Carolina at Chapel Hill (US), University of Southern California (US), Brigham and Women's Hospital (US), Pennsylvania State University (US), Cancer Prevention Institute of California (US), Harvard University (US), Johns Hopkins University (US), Emory University (US), University of Pittsburgh (US), University of Toronto (CA), University of Michigan (US), Johns Hopkins Medicine (US), Leiden University Medical Center (NL), Montreal Heart Institute (CA), Novo Nordisk Foundation (DK), VA Boston Healthcare System (US), Fred Hutch Cancer Center (US), Neurobehavioral Systems (US), Michigan United (US), Child Health and Development Institute (US), Brownsville Public Library (US), Brown Foundation (US), Hospital de Especialidades (MX), Atlanta VA Health Care System (US), Institute for Social Research (NO), University of Virginia (US), Geisinger Health System (US), Vanderbilt University Medical Center (US), The University of Texas Health Science Center at Houston (US), University of Colorado Denver (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Veterans Affairs, National Cancer Institute, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Openalex Percentile: Top 4%
Genetic Associations and Epidemiology
5.45
DOIOpen Access PDFOpenAlex
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