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

作者：Mohanraj Krishnan, Mohammad Yaser Anwar, Anne E. Justice, Geetha Chittoor, Hung‐Hsin Chen, Rashedeh Roshani, Alyssa Scartozzi, R. Dickerson, Roelof A. J. Smit, Michael H Preuss, Nathalie Chami, Benjamin S Hadad, Esteban J. Parra, Miguel Cruz, Qin Hui, Peter W F Wilson, Yan V. Sun, Xiaoyu Zhang, Gregorio V. Linchangco, Sharon L. R. Kardia, Jessica D. Faul, David R. Weir, Lawrence F. Bielak, Heather M. Highland, Kristin L. Young, Baiyu Qi, Yujie Wang, Myriam Fornage, Christopher Haiman, Iona Cheng, Ulrike Peters, Charles Kooperberg, Steven Buyske, Joseph B. McCormick, Susan P. Fisher‐Hoch, Frida Lona‐Durazo, Jesús Peralta, Jamie Gomez-Zamudio, Stephen S. Rich, Kendra Ferrier, Ethan M. Lange, Christopher R. Gignoux, Eimear E. Kenny, Genevieve L. Wojcik, Kelly Cho, Michael Gaziano, Luc Djoussé, Shuwei Liu, Dhananjay Vaidya, Renée de Mutsert, Navya Shilpa Josyula, Chr. Bauer, Wei Zhao, Ryan W. Walker, Jennifer A. Smith, Leslie A. Lange, Mariah Meyer, Ching‐Ti Liu, Lisa R. Yanek, Miryoung Lee, Laura M. Raffield, Ruth J. F. Loos, Penny Gordon‐Larsen, Jennifer E Below, Kari E North, Mariaelisa Graff · 发表于：PLoS Genetics · 年份：2025 · DOI：10.1371/journal.pgen.1011842 · 被引用次数：4 · 研究领域：Genetic Associations and Epidemiology、Genetic and phenotypic traits in livestock、Cancer-related molecular mechanisms research

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 clini...