Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10-6) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10-26) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10-11) and one near SPRY2 (P = 3 × 10-8). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

Additional Metadata
Persistent URL dx.doi.org/10.1038/ng.866, hdl.handle.net/1765/34179
Journal Nature Genetics
Note Free full text at PubMed
Grant This work was funded by the European Commission 7th Framework Programme; grant id fp7/266408 - Understanding food-gut-brain mechanisms across the lifespan in the regulation of hunger and satiety for health (FULL4HEALTH), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201681 - NOVEL PREP1-DEPENDENT TRANSCRIPTIONAL NETWORKS IN THE CONTROL OF INSULIN SENSITIVITY (PREPOBEDIA), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201865 - GENETIC FACTORS FOR OSTEOPOROSIS (GEFOS), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201413 - European Network for Genetic and Genomic Epidemiology (ENGAGE), This work was funded by the European Commission 7th Framework Programme; grant id fp7/201550 - European Network for Genetic-Epidemiological Studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model (HYPERGENES)
Citation
Kilpeläinen, T.O, Zillikens, M.C, Stancáková, A, Finucane, F.M, Ried, J.S, Langenberg, C, … Aulchenko, Y.S. (2011). Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics, 43(8), 753–760. doi:10.1038/ng.866