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

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 asso...

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Veröffentlicht in:	Nature (London) Jg. 518; H. 7538; S. 187 - 196
Hauptverfasser:	Ferreira, Teresa, Locke, Adam E., Justice, Anne E., Wu, Joseph M. W., Buchkovich, Martin L., Heard-Costa, Nancy L., Drong, Alexander W., Gustafsson, Stefan, Fall, Tove, Scherag, André, Absher, Devin, Ehret, Georg B., Kleber, Marcus E., Peters, Marjolein J., Albrecht, Eva, Bellis, Claire, Böhringer, Stefan, Böttcher, Yvonne, Clarke, Robert, Eklund, Niina, Erdos, Michael R., Estrada, Karol, Eury, Elodie, Friedrich, Nele, Giedraitis, Vilmantas, Gigante, Bruna, Go, Alan S., Hallmans, Goran, Hassinen, Maija, Hunt, Steven C., Koenig, Wolfgang, Kratzer, Wolfgang, Lindström, Jaana, Merger, Sigrun, Mihailov, Evelin, Mills, Rebecca, Moayyeri, Alireza, Müller-Nurasyid, Martina, Nalls, Michael A., Narisu, Narisu, Nolte, Ilja M., Sanna, Serena, Seufferlein, Thomas, Wennauer, Roman, Choi, Murim, Karpe, Fredrik, Keildson, Sarah, Kiryluk, Krzysztof, Lifton, Richard P., Ma, Baoshan, Nicholson, George, Schadt, Eric E., Scott, Robert A., Westra, Harm-Jan, Beilby, John, Bergman, Richard N., Brown, Morris J., Campbell, Harry, Danesh, John, de Geus, Eco J. C., Ferrannini, Ele, Ferrières, Jean, Haiman, Christopher A., Johansen, Berit, Jousilahti, Pekka, Keinanen-Kiukaanniemi, Sirkka M., Kooperberg, Charles, Kumari, Meena, Matise, Tara C., Möhlenkamp, Stefan, Nelis, Mari, Ong, Ken K., Palmer, Lyle J., Ritchie, Marylyn D., Salomaa, Veikko, Samani, Nilesh J., Saramies, Jouko, Sarzynski, Mark A., Schwarz, Peter E. H., Strauch, Konstantin, Boehm, Bernhard O., Chambers, John C., Grabe, Hans-Jörgen, Hamsten, Anders, Kivimaki, Mika, März, Winfried, Pedersen, Nancy L., Pérusse, Louis, Power, Chris, Rauramaa, Rainer, Rivadeneira, Fernando, Thorsteinsdottir, Unnur, Stumvoll, Michael, Watkins, Hugh, Wichmann, H-Erich, Hunter, David J., Qi, Lu, Speliotes, Elizabeth K., Fox, Caroline S., Barroso, Inês
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 12.02.2015 Nature Publishing Group
Schlagworte:	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 Europe Sweden
ISSN:	0028-0836, 1476-4687, 1476-4687
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC4338562 These authors jointly directed this work. Author Contributions See the Supplementary Note for Author Contributions. Author Information Summary results are available at http://www.broadinstitute.org/collaboration/giant/. G.T., V.S., U.T., and K.S. are employed by deCODE Genetics/Amgen, Inc. I.B. and spouse own stock in GlaxoSmithKline and Incyte, Ltd. C.B. is a consultant for Weight Watchers, Pathway Genomics, NIKE, and Gatorade PepsiCo.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/nature14132