Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Original publication

DOI

10.1038/nature14132

Type

Journal article

Journal

Nature

Publication Date

02/2015

Volume

518

Pages

187 - 196

Addresses

Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå 901 87, Sweden.

Keywords

ADIPOGen Consortium, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GEFOS Consortium, GENIE Consortium, GLGC, ICBP, International Endogene Consortium, LifeLines Cohort Study, MAGIC Investigators, MuTHER Consortium, PAGE Consortium, ReproGen Consortium, Adipose Tissue, Adipocytes, Humans, Insulin Resistance, Obesity, Insulin, Body Mass Index, Waist-Hip Ratio, Age Factors, Transcription, Genetic, Epigenesis, Genetic, Sex Characteristics, Neovascularization, Physiologic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome, Human, Models, Biological, Continental Population Groups, Europe, Female, Male, Adipogenesis, Body Fat Distribution, Genome-Wide Association Study