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

Not all individuals with obesity develop cardiometabolic complications. Huang et al. use genome-wide meta-analysis to identify genetic loci associated with lower cardiometabolic risk despite increased adiposity. 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.

Automated summary

This study identified genetic loci associated with higher obesity risk and lower cardiometabolic risk, highlighting the role of genes expressed in adipose tissue and influencing adipocyte function. Various mechanisms including insulin-glucose signaling, energy expenditure, white adipose tissue browning, and inflammation were involved. Some of these genes may serve as potential therapeutic targets for reducing cardiometabolic risk associated with excess adiposity.