TY - JOUR
T1 - Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities
AU - Huang, Lam O
AU - Rauch, Alexander
AU - Mazzaferro, Eugenia
AU - Preuss, Michael
AU - Carobbio, Stefania
AU - Bayrak, Cigdem S
AU - Chami, Nathalie
AU - Wang, Zhe
AU - Schick, Ursula M
AU - Yang, Nancy
AU - Itan, Yuval
AU - Vidal-Puig, Antonio
AU - den Hoed, Marcel
AU - Mandrup, Susanne
AU - Kilpeläinen, Tuomas O
AU - Loos, Ruth J F
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Adipocytes/metabolism
KW - Adipocytes, Brown/physiology
KW - Adipocytes, White/physiology
KW - Adipose Tissue/metabolism
KW - Adiposity/genetics
KW - Alleles
KW - Energy Metabolism/physiology
KW - Fatty Acids/metabolism
KW - Genetic Loci/genetics
KW - Genome-Wide Association Study
KW - Glucose/metabolism
KW - Humans
KW - Insulin/metabolism
KW - Multigene Family/genetics
KW - Obesity/complications
KW - Risk Assessment
KW - Signal Transduction/physiology
UR - http://www.scopus.com/inward/record.url?scp=85101301590&partnerID=8YFLogxK
U2 - 10.1038/s42255-021-00346-2
DO - 10.1038/s42255-021-00346-2
M3 - Journal article
C2 - 33619380
SN - 2522-5812
VL - 3
SP - 228
EP - 243
JO - Nature metabolism
JF - Nature metabolism
IS - 2
ER -