Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities

Lam O. Huang, Alexander Rauch, Eugenia Mazzaferro, Michael Preuss, Stefania Carobbio, Cigdem S. Bayrak, Nathalie Chami, Zhe Wang, Ursula M. Schick, Nancy Yang, Yuval Itan, Antonio Vidal-Puig, Marcel den Hoed, Susanne Mandrup, Tuomas O. Kilpeläinen, Ruth J.F. Loos*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review


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.

Original languageEnglish
JournalNature Metabolism
Issue number2
Pages (from-to)228-243
Publication statusPublished - Feb 2021


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