Obesity is a major risk factor for cardiometabolic diseases. Nevertheless, a substantial proportion of individuals with obesity do not suffer cardiometabolic comorbidities. The mechanisms that uncouple adiposity from its cardiometabolic complications are not fully understood. Here, we identify 62 loci of which the same allele is significantly associated with both higher adiposity and lower cardiometabolic risk. Functional analyses show that the 62 loci are enriched for genes expressed in adipose tissue, and for regulatory variants that influence nearby genes that affect adipocyte differentiation. Genes prioritized in each locus support a key role of fat distribution (FAM13A, IRS1 and PPARG) and adipocyte function (ALDH2, CCDC92, DNAH10, ESR1, FAM13A, MTOR, PIK3R1 and VEGFB). Several additional mechanisms are involved as well, such as insulin–glucose signalling (ADCY5, ARAP1, CREBBP, FAM13A, MTOR, PEPD, RAC1 and SH2B3), energy expenditure and fatty acid oxidation (IGF2BP2), browning of white adipose tissue (CSK, VEGFA, VEGFB and SLC22A3) and inflammation (SH2B3, DAGLB and ADCY9). Some of these genes may represent therapeutic targets to reduce cardiometabolic risk linked to excess adiposity.
Bibliografisk noteFunding Information:
R.J.F.L. is supported by the National Institutes of health (NIH; R01DK11011, R01DK107786 and R01DK124097). T.O.K. is supported by the Independent Research Fund Denmark (6110-00183) and the Novo Nordisk Foundation (NNF17OC0026848, NNF18CC0034900 and NNF20OC0063707). M.d.H. is a fellow of the Swedish Heart-Lung Foundation (20170872 and 20200781) and a Kjell and Märta Beijer Foundation researcher. M.d.H. is further supported by the Swedish Heart-Lung Foundation (20140543, 20170678, 20180706 and 20200602) and the Swedish Research Council (2015-03657 and 2019-01417). A.V.-P. is supported by NIH R01DK107786, an ERC Senior Investigator award (669879) and an MRC MDU Programme grant (PO 4050281695). Yuval Itan is supported by the NIH (R01DK123530). The work of A.R. and S.M. was supported by grants from the Independent Research Fund Denmark (Sapere Aude Advanced grant no. 12-125524), the Danish National Research Foundation (grant no. 141) to the Center for Functional Genomics and Tissue Plasticity and the Novo Nordisk Foundation. A.R. was further supported by a postdoctoral grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation. N.C. is supported by a grant from the Canadian Institutes of Health Research (fellowship MFE-158192).
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