Journal Article

New genetic loci link adipose and insulin biology to body fat distribution

Kumari, Meena, Kaplan, Robert C., Fox, Caroline S., Assimes, Themistocles L., Franks, Paul W., McKnight, Barbara, Sanna, Serena, Amin, Najaf, Stolk, Lisette, Kahali, Bratati, Jackson, Anne U., Buchkovich, Martin L., Peters, Annette, Palmer, Colin N. A., Esko, Tonu, Kaprio, Jaakko, Njølstad, Inger, Borecki, Ingrid B., Sitlani, Colleen M., Qi, Lu, Monda, Keri L., Liu, Ching-Ti, Forouhi, Nita G., Cooper, Richard S., Tönjes, Anke, Barroso, Inês, Berne, Christian, Bochud, Murielle, Nalls, Michael A., Lind, Lars, Vedantam, Sailaja, Deelman, Ewa, Perry, John R. B., Johansson, Ingegerd, Palmer, Lyle J., Frayling, Timothy M., Wood, Andrew R., Kooperberg, Charles, Lindström, Jaana, Gharavi, Ali G., Gigante, Bruna, Holmen, Oddgeir, Friedrich, Nele, Jarvelin, Marjo-Riitta, Wichmann, H-Erich, Möhlenkamp, Stefan, Goel, Anuj, Kratzer, Wolfgang, Sarzynski, Mark A., Erdos, Michael R., Schadt, Eric E., Syvänen, Ann-Christine, Pechlivanis, Sonali, März, Winfried, Strachan, David P., Salomaa, Veikko, Salem, Rany M., Bergman, Richard N., Kraja, Aldi T., Ingelsson, Erik, Wojczynski, Mary K., Musk, Arthur W., Workalemahu, Tsegase

2015

Overview

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. Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution. Cardiometabolic traits linked to body fat distribution In the first of a pair of Articles in this issue from the GIANT Consortium, genome-wide association meta-analyses of waist and hip circumference-related traits in more than 200,000 individuals have been used to identify 49 loci — 33 of them new — associated with waist-to-hip ratio adjusted for body mass index and an additional 19 loci associated with related waist and hip circumference measures. A subset of these loci shows significant sexual dimorphism, with many showing a stronger effect in women. Analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms and offer potential targets for interventions in the risks associated with abdominal fat accumulation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/43 / 631/208/205/2138 / Abdomen / Adipocytes - metabolism / Adipocytes/metabolism Adipogenesis/genetics Adipose Tissue/metabolism Age Factors Body Fat Distribution Body Mass Index Continental Population Groups/genetics Epigenesis, Genetic Europe/ethnology Female Genome, Human/genetics Genome-Wide Association Study Humans Insulin/metabolism Insulin Resistance/genetics Male Models, Biological Neovascularization, Physiologic/genetics Obesity/genetics Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics Sex Characteristics Transcription, Genetic/genetics Waist-Hip Ratio / Adipogenesis - genetics / Adipose tissue / Adipose Tissue - metabolism / Adipose tissues / Age Factors / Body fat / Body Fat Distribution / Body Mass Index / Clinical Medicine / Discovery and exploration / Distribution / Endocrinology and Diabetes / Endokrinologi och diabetes / Epigenesis, Genetic / Europe - ethnology / Female / Folkhälsovetenskap, global hälsa och socialmedicin / Genealogy / Genetic aspects / Genetic research / Genetics / Genome, Human - genetics / Genome-Wide Association Study / Genomes / Health and Welfare / Health aspects / Humanities and Social Sciences / Humans / Hälsa och välfärd / Insulin / Insulin - metabolism / Insulin resistance / Insulin Resistance - genetics / Klinisk medicin / Life Sciences / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Meta-analysis / Metabolism / Models, Biological / multidisciplinary / Neovascularization, Physiologic - genetics / Obesity - genetics / Physiological aspects / Polymorphism, Single Nucleotide - genetics / Public Health, Global Health and Social Medicine / Quantitative trait loci / Quantitative Trait Loci - genetics / Racial Groups - genetics / Science / Sex Characteristics / Studies / Transcription, Genetic - genetics / Waist-Hip Ratio