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

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Abstract

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, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures ( P<5×10 ⁻⁸). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed 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.

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Most cited references 48

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Identifying ChIP-seq enrichment using MACS.

Jianxing Feng, Tao Liu, Bo Qin … (2012)

Model-based analysis of ChIP-seq (MACS) is a computational algorithm that identifies genome-wide locations of transcription/chromatin factor binding or histone modification from ChIP-seq data. MACS consists of four steps: removing redundant reads, adjusting read position, calculating peak enrichment and estimating the empirical false discovery rate (FDR). In this protocol, we provide a detailed demonstration of how to install MACS and how to use it to analyze three common types of ChIP-seq data sets with different characteristics: the sequence-specific transcription factor FoxA1, the histone modification mark H3K4me3 with sharp enrichment and the H3K36me3 mark with broad enrichment. We also explain how to interpret and visualize the results of MACS analyses. The algorithm requires ∼3 GB of RAM and 1.5 h of computing time to analyze a ChIP-seq data set containing 30 million reads, an estimate that increases with sequence coverage. MACS is open source and is available from http://liulab.dfci.harvard.edu/MACS/.

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A human phenome-interactome network of protein complexes implicated in genetic disorders.

Kasper Lage, E Olof Karlberg, Zenia Størling … (2007)

We performed a systematic, large-scale analysis of human protein complexes comprising gene products implicated in many different categories of human disease to create a phenome-interactome network. This was done by integrating quality-controlled interactions of human proteins with a validated, computationally derived phenotype similarity score, permitting identification of previously unknown complexes likely to be associated with disease. Using a phenomic ranking of protein complexes linked to human disease, we developed a Bayesian predictor that in 298 of 669 linkage intervals correctly ranks the known disease-causing protein as the top candidate, and in 870 intervals with no identified disease-causing gene, provides novel candidates implicated in disorders such as retinitis pigmentosa, epithelial ovarian cancer, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer disease, type 2 diabetes and coronary heart disease. Our publicly available draft of protein complexes associated with pathology comprises 506 complexes, which reveal functional relationships between disease-promoting genes that will inform future experimentation.

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Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men.

Youfa Wang, Eric Rimm, Meir J. Stampfer … (2005)

Obesity is a strong risk factor for type 2 diabetes. However, few studies have compared the predictive power of overall obesity with that of central obesity. The cutoffs for waist circumference (WC) and waist-to-hip ratio (WHR) as measures of abdominal adiposity remain controversial. The objective was to compare body mass index (BMI), WC, and WHR in predicting type 2 diabetes. A prospective cohort study (Health Professionals Follow-Up Study) of 27 270 men was conducted. WC, WHR, and BMI were assessed at baseline. Covariates and potential confounders were assessed repeatedly during the follow-up. During 13 y of follow-up, we documented 884 incident type 2 diabetes cases. Age-adjusted relative risks (RRs) across quintiles of WC were 1.0, 2.0, 2.7, 5.0, and 12.0; those of WHR were 1.0, 2.1, 2.7, 3.6, and 6.9; and those of BMI were 1.0, 1.1, 1.8, 2.9, and 7.9 (P for trend /=24.8), WC (>/=94 cm), and WHR (>/=0.94) were 82.5%, 83.6%, and 74.1%, respectively. The corresponding proportions were 78.9%, 50.5%, and 65.7% according to the recommended cutoffs. Both overall and abdominal adiposity strongly and independently predict risk of type 2 diabetes. WC is a better predictor than is WHR. The currently recommended cutoff for WC of 102 cm for men may need to be reevaluated; a lower cutoff may be more appropriate.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 16 December 2014

Publication date (Print): 12 February 2015

Publication date PMC-release: 12 August 2015

Volume: 518

Issue: 7538

Pages: 187-196

Affiliations

[1 ]Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå 901 87, Sweden

[2 ]Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hosptial, Malmö 205 02, Sweden

[3 ]Department of Odontology, Umeå University, Umeå 901 85, Sweden

[4 ]Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, D-93053 Regensburg, Germany

[5 ]Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA

[6 ]Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA

[7 ]Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK

[8 ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA

[9 ]Estonian Genome Center, University of Tartu, Tartu 51010, Estonia

[10 ]Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm 17176, Sweden

[11 ]Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA 02115, USA

[12 ]Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge 02142, MA, USA

[13 ]Department of Genetics, Harvard Medical School, Boston, MA 02115, USA

[14 ]Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark

[15 ]Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

[16 ]Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

[17 ]Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA

[18 ]National Heart, Lung, and Blood Institute, the Framingham Heart Study, Framingham MA 01702, USA

[19 ]Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA

[20 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden

[21 ]Science for Life Laboratory, Uppsala University, Uppsala 75185, Sweden

[22 ]Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75185, Sweden

[23 ]MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK

[24 ]Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne 1010, Switzerland

[25 ]Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland

[26 ]Department of Medical Genetics, University of Lausanne, Lausanne 1005, Switzerland

[27 ]Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK

[28 ]Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, Germany

[29 ]Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany

[30 ]Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK

[31 ]Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA

[32 ]Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

[33 ]Department of Internal Medicine, Division of Gastroenterology, and Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109

[34 ]Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

[35 ]HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA

[36 ]Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC University Medical Center, 3015 GE Rotterdam, The Netherlands

[37 ]Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Perth, Western Australia 6008, Australia

[38 ]Netherlands Consortium for Healthy Aging (NCHA), Leiden University Medical Center, Leiden 2300 RC, The Netherlands

[39 ]Department of Molecular Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

[40 ]Kidney Epidemiology and Cost Center, University of Michigan, Ann Arbor, MI 48109

[41 ]Department of Statistics & Biostatistics, Rutgers University, Piscataway, NJ USA

[42 ]Department of Genetics, Rutgers University, Piscataway, NJ USA

[43 ]Department of Human Genetics, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands

[44 ]Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

[45 ]Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland

[46 ]Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA

[47 ]Division of Cardiovacular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK

[48 ]University Institute for Social and Preventative Medecine, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne 1005, Switzerland

[49 ]Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Germany

[50 ]Department of Internal Medicine II, Ulm University Medical Centre, D-89081 Ulm, Germany

[51 ]National Institute for Health and Welfare, FI-00271 Helsinki, Finland

[52 ]Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK

[53 ]Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands

[54 ]Netherlands Consortium for Healthy Aging (NCHA), 3015GE Rotterdam, The Netherlands

[55 ]Department of Epidemiology, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands

[56 ]Department of Internal Medicine, Erasmus MC University Medical Center, 3015GE Rotterdam, The Netherlands

[57 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK

[58 ]Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK

[59 ]University of Eastern Finland, FI-70210 Kuopio, Finland

[60 ]Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA

[61 ]Translational Gerontology Branch, National Institute on Aging, Baltimore MD 21225, USA

[62 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany

[63 ]Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, 9700 RB, The Netherlands

[64 ]CNRS UMR 8199, F-59019 Lille, France

[65 ]European Genomic Institute for Diabetes, F-59000 Lille, France

[66 ]Université de Lille 2, F-59000 Lille, France

[67 ]Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK

[68 ]Department of Epidemiology and Biostatistics, Imperial College London, London W2 1PG, UK

[69 ]Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany

[70 ]School of Health and Social Studies, Dalarna University, Falun, Sweden

[71 ]PathWest Laboratory Medicine of Western Australia, NEDLANDS, Western Australia 6009, Australia

[72 ]Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy

[73 ]Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA

[74 ]Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

[75 ]Department of Medical Sciences, Endocrinology, Diabetes and Metabolism, Uppsala University, Uppsala 75185, Sweden

[76 ]Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, D-04103 Leipzig, Germany

[77 ]Department of Medicine, University of Leipzig, D-04103 Leipzig, Germany

[78 ]Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

[79 ]Inserm UMR991, Department of Endocrinology, University of Rennes, F-35000 Rennes, France

[80 ]LifeLines Cohort Study, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

[81 ]USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City 6000, Philippines

[82 ]Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway

[83 ]Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK

[84 ]Information Sciences Institute, University of Southern California, Marina del Rey, California, USA

[85 ]Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK

[86 ]Institute for Molecular Medicine, University of Helsinki, FI-00014 Helsinki, Finland

[87 ]Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA

[88 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

[89 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany

[90 ]Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Bethesda, MD 20892, USA

[91 ]Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala 75185, Sweden

[92 ]Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, Stockholm 17177, Sweden

[93 ]Kaiser Permanente, Division of Research, Oakland, CA 94612, USA

[94 ]Service of Therapeutic Education for Diabetes, Obesity and Chronic Diseases, Geneva University Hospital, Geneva CH-1211, Switzerland

[95 ]Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany

[96 ]German Center for Diabetes Research (DZD), Neuherberg, Germany

[97 ]Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany

[98 ]Department of Public Health and Clinical Medicine, Unit of Nutritional Research, Umeå University, Umeå 90187, Sweden

[99 ]Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

[100 ]Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

[101 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XU, Scotland, UK

[102 ]Hjelt Institute Department of Public Health, University of Helsinki, FI-00014 Helsinki, Finland

[103 ]Institute of Biomedicine, University of Oulu, Oulu, Finland

[104 ]Medical Research Center Oulu and Oulu University Hospital, Oulu, Finland

[105 ]Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland

[106 ]Faculty of Psychology and Education, VU University Amsterdam, Amsterdam, The Netherlands

[107 ]Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

[108 ]Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim 7489, Norway

[109 ]Cardiovascular Genetics Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84108, USA

[110 ]Center for Medical Sytems Biology, Leiden, The Netherlands

[111 ]Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany

[112 ]Department of Pulmonary Physiology and Sleep Medicine, Nedlands, Western Australia 6009, Australia

[113 ]School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia

[114 ]Department of Dietetics-Nutrition, Harokopio University, Athens, Greece

[115 ]Department of Internal Medicine I, Ulm University Medical Centre, D-89081 Ulm, Germany

[116 ]Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, 6020 Innsbruck, Austria

[117 ]Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany

[118 ]Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 75185, Sweden

[119 ]Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg 413 45, Sweden

[120 ]School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK

[121 ]Division of Endocrinology, Diabetes and Metabolism, Ulm University Medical Centre, D-89081 Ulm, Germany

[122 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia

[123 ]Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK

[124 ]The Center for Observational Research, Amgen, Inc., Thousand Oaks, CA 91320, USA

[125 ]Department of Gerontology and Geriatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands

[126 ]Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

[127 ]Institute of Human Genetics, University of Bonn, Bonn, Germany

[128 ]Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, Cagliari, Sardinia 09042, Italy

[129 ]Center for Evidence-based Healthcare, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany

[130 ]Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, D-81377 Munich, Germany

[131 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, D-81377 Munich, Germany

[132 ]Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK) (German Research Centre for Cardiovascular Research), Munich Heart Alliance, D-80636 Munich, Germany

[133 ]Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA

[134 ]Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA

[135 ]Hypertension and Related Diseases Centre - AOU, University of Sassari Medical School, Sassari 07100, Italy

[136 ]Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA

[137 ]Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria

[138 ]Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden

[139 ]Department of Medicine, University of Washington, Seattle, WA 98101, USA

[140 ]Icelandic Heart Association, Kopavogur 201, Iceland

[141 ]University of Iceland, Reykjavik 101, Iceland

[142 ]William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ UK

[143 ]Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala 75144, Sweden

[144 ]Department of Public Health Sciences, Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 61053, USA

[145 ]Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany

[146 ]deCODE Genetics, Amgen inc., Reykjavik 101, Iceland

[147 ]Department of Cardiology, Medical University of Graz, Graz 8036, Austria

[148 ]Department of Child and Adolescent Psychiatry, Psychology, Erasmus MC University Medical Centre, 3000 CB Rotterdam, The Netherlands

[149 ]Department of Clinical Chemistry, Ulm University Medical Centre, D-89081 Ulm, Germany

[150 ]Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway

[151 ]MRC Unit for Lifelong Health and Ageing at University College London, London WC1B 5JU, UK

[152 ]Diabetes Complications Research Centre, Conway Institute, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland

[153 ]Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea

[154 ]Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden

[155 ]Department of Medicine, Columbia University College of Physicians and Surgeons, New York NY, USA

[156 ]Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA

[157 ]Massachusetts General Hospital, Boston, MA, USA

[158 ]State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China

[159 ]Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA

[160 ]NIHR Oxford Biomedical Research Centre, OUH Trust, Oxford OX3 7LE, UK

[161 ]Harvard School of Public Health, Department of Biostatistics, Harvard University, Boston, MA 2115, USA

[162 ]Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, New Haven CT, USA

[163 ]College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning 116026, China

[164 ]Nephrology Research, Centre for Public Health, Queen’s University of Belfast, Belfast, Co. Down BT9 7AB, UK

[165 ]University of Ottawa Heart Institute, Ottawa K1Y 4W7, Canada

[166 ]National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK

[167 ]QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia

[168 ]Section of General Internal Medicine, Boston University School of Medicine, Boston, MA 02118, USA

[169 ]Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK

[170 ]MRC Harwell, Harwell Science and Innovation Campus, Harwell, UK

[171 ]Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland 4059, Australia

[172 ]Department of Biomedical Engineering and Computational Science, Aalto University School of Science, Helsinki, Finland

[173 ]Department of Medicine, Division of Nephrology, Helsinki University Central Hospital, FI-00290 Helsinki, Finland

[174 ]Folkhälsan Institute of Genetics, Folkhälsan Research Center, FI-00290 Helsinki, Finland

[175 ]Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10580, USA

[176 ]Computer Science Department, Tecnológico de Monterrey, Atizapán de Zaragoza, 52926, Mexico

[177 ]Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford OX3 7BN, UK

[178 ]Adiponectin Genetic Consortium

[179 ]Membership to this consortium is provided below

[180 ]The GEnetic Factors for OSteoporosis Consortium

[181 ]GEnetics of Nephropathy - an International Effort Consortium

[182 ]The Global Lipids Genetics Consortium

[183 ]The International Consortium for Blood Pressure Genome-Wide Association Studies

[184 ]The LifeLines Cohort Study, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

[185 ]Meta-Analyses of Glucose and Insulin-related traits Consortium Investigators

[186 ]The Multiple Tissue Human Expression Resource Consortium

[187 ]Population Architecture using Genomics and Epidemiology Consortium

[188 ]Institut Pasteur de Lille; INSERM, U744; Université de Lille 2; F-59000 Lille, France

[189 ]Department of Epidemiology and Public Health, EA3430, University of Strasbourg, Faculty of Medicine, Strasbourg, France

[190 ]Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700RB Groningen, The Netherlands

[191 ]Pathology and Laboratory Medicine, The University of Western Australia, Perth, Western Australia 6009, Australia

[192 ]Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, CA, USA

[193 ]Clinical Pharmacology Unit, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK

[194 ]Service of Nephrology, Department of Medicine, Lausanne University Hospital (CHUV), Lausanne 1005, Switzerland

[195 ]Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, Scotland, UK

[196 ]Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville TN 37203, USA

[197 ]Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA

[198 ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

[199 ]Biological Psychology, VU University Amsterdam, 1081BT Amsterdam, The Netherlands

[200 ]Institute for Research in Extramural Medicine, Institute for Health and Care Research, VU University, 1081BT Amsterdam, The Netherlands

[201 ]Department of Internal Medicine B, University Medicine Greifswald, D-17475 Greifswald, Germany

[202 ]DZHK (Deutsches Zentrum für Herz-Kreislaufforschung – German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany

[203 ]Clinic of Cardiology, West-German Heart Centre, University Hospital Essen, Essen, Germany

[204 ]Department of General Practice and Primary Health Care, University of Helsinki, FI-00290 Helsinki, Finland

[205 ]Unit of General Practice, Helsinki University Central Hospital, Helsinki 00290, Finland

[206 ]Department of Internal Medicine, University of Pisa, Pisa, Italy

[207 ]National Research Council Institute of Clinical Physiology, University of Pisa, Pisa, Italy

[208 ]Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France

[209 ]UWI Solutions for Developing Countries, The University of the West Indies, Mona, Kingston 7, Jamaica

[210 ]Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

[211 ]Institute of Biomedical & Clinical Science, University of Exeter, Barrack Road, Exeter EX2 5DW, UK

[212 ]Center for Biomedicine, European Academy Bozen, Bolzano (EURAC), Bolzano 39100, Italy - Affiliated Institute of the University of Lübeck, D-23562 Lübeck, Germany

[213 ]Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK

[214 ]Centre for Cardiovascular Genetics, Institute Cardiovascular Sciences, University College London, London WC1E 6JJ, UK

[215 ]Sansom Institute for Health Research, University of South Australia, Adelaide 5000, South Australia, Australia

[216 ]School of Population Health, University of South Australia, Adelaide 5000, South Australia, Australia

[217 ]South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

[218 ]Population, Policy, and Practice, University College London Institute of Child Health, London WC1N 1EH, UK

[219 ]Hannover Unified Biobank, Hannover Medical School, Hannover, D-30625 Hannover, Germany

[220 ]National Institute for Health and Welfare, FI-90101 Oulu, Finland

[221 ]MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, UK

[222 ]Unit of Primary Care, Oulu University Hospital, FI-90220 Oulu, Finland

[223 ]Institute of Health Sciences, FI-90014 University of Oulu, Finland

[224 ]UK Clinical Research Collaboration Centre of Excellence for Public Health (NI), Queens University of Belfast, Belfast, Northern Ireland

[225 ]Institute of Health Sciences, Faculty of Medicine, University of Oulu, Oulu, Finland

[226 ]Unit of Primary Health Care/General Practice, Oulu University Hospital, Oulu, Finland

[227 ]Imperial College Healthcare NHS Trust, London W12 0HS, UK

[228 ]Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

[229 ]Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK

[230 ]Department of Biological and Social Epidemiology, University of Essex, Wivenhoe Park, Colchester, Essex, CO4 3SQ, UK

[231 ]Department of Medicine, Kuopio University Hospital and University of Eastern Finland, FI-70210 Kuopio, Finland

[232 ]Department of Physiology, Institute of Biomedicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland

[233 ]Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland

[234 ]Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI USA

[235 ]Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine University of Tampere, FI-33520 Tampere, Finland

[236 ]Steno Diabetes Center A/S, Gentofte DK-2820, Denmark

[237 ]Lund University Diabetes Centre and Department of Clinical Science, Diabetes & Endocrinology Unit, Lund University, Malmö 221 00, Sweden

[238 ]Institut Universitaire de Cardiologie et de Pneumologie de Québec, Faculty of Medicine, Laval University, Quebec, QC G1V 0A6, Canada

[239 ]Institute of Nutrition and Functional Foods, Laval University, Quebec, QC G1V 0A6, Canada

[240 ]Department of Biostatistics, University of Washington, Seattle, WA 98195, USA

[241 ]Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia

[242 ]Epidemiology and Obstetrics & Gynaecology, University of Toronto, Toronto, Ontario, Canada

[243 ]Genetic Epidemiology & Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada

[244 ]Department of Psychiatry, Neuroscience Campus, VU University Amsterdam, Amsterdam, The Netherlands

[245 ]Department of Neurology, General Central Hospital, Bolzano 39100, Italy

[246 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, FI-20521 Turku, Finland

[247 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, FI-20521 Turku, Finland

[248 ]Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA

[249 ]Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA

[250 ]Harvard Medical School, Boston, MA 02115, USA

[251 ]Center for Systems Genomics, The Pennsylvania State University, University Park, PA 16802, USA

[252 ]Croatian Centre for Global Health, Faculty of Medicine, University of Split, 21000 Split, Croatia

[253 ]Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK

[254 ]National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK

[255 ]South Carelia Central Hospital, 53130 Lappeenranta, Finland

[256 ]Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany

[257 ]Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA

[258 ]Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

[259 ]Geriatric Research and Education Clinical Center, Vetrans Administration Medical Center, Baltimore, MD 21201, USA

[260 ]Department of Epidemiology, Maastricht University, Maastricht, The Netherlands

[261 ]Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, B-3000 Leuven, Belgium

[262 ]Department of Kinesiology, Laval University, Quebec, QC G1V 0A6, Canada

[263 ]Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano & Centro Cardiologico Monzino, Instituto di Ricovero e Cura a Carattere Scientifico, Milan 20133, italy

[264 ]Department of Food Science and Nutrition, Laval University, Quebec, QC G1V 0A6, Canada

[265 ]Department of Internal Medicine, University Hospital (CHUV) and University of Lausanne, 1011, Switzerland

[266 ]Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA

[267 ]Institute of Social and Preventive Medicine (IUMSP), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

[268 ]Ministry of Health, Victoria, Republic of Seychelles

[269 ]Lee Kong Chian School of Medicine, Imperial College London and Nanyang Technological University, Singapore, 637553 Singapore, Singapore

[270 ]Department of Internal Medicine I, Ulm University Medical Centre, D-89081 Ulm, Germany

[271 ]Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK

[272 ]Department of Psychiatry and Psychotherapy, University Medicine Greifswald, HELIOS-Hospital Stralsund, D-17475 Greifswald, Germany

[273 ]German Center for Neurodegenerative Diseases (DZNE), Rostock, Greifswald, D-17475 Greifswald, Germany

[274 ]School of Population Health, The University of Western Australia, Nedlands, Western Australia 6009, Australia

[275 ]Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

[276 ]Synlab Academy, Synlab Services GmbH, Mannheim, Germany

[277 ]Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands

[278 ]Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA

[279 ]Finnish Diabetes Association, Kirjoniementie 15, FI-33680 Tampere, Finland

[280 ]Pirkanmaa Hospital District, Tampere, Finland

[281 ]Center for Non-Communicable Diseases, Karatchi, Pakistan

[282 ]Department of Medicine, University of Pennsylvania, Philadelphia, USA

[283 ]Helsinki University Central Hospital Heart and Lung Center, Department of Medicine, Helsinki University Central Hospital, FI-00290 Helsinki, Finland

[284 ]Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland

[285 ]Instituto de Investigacion Sanitaria del Hospital Universario LaPaz (IdiPAZ), Madrid, Spain

[286 ]Diabetes Research Group, King Abdulaziz University, 21589 Jeddah, Saudi Arabia

[287 ]Centre for Vascular Prevention, Danube-University Krems, 3500 Krems, Austria

[288 ]Department of Public Health and Clinical Nutrition, University of Eastern Finland, Finland

[289 ]Research Unit, Kuopio University Hospital, Kuopio, Finland

[290 ]Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute Netherlands-Netherlands Heart Institute, 3501 DG Utrecht, The Netherlands

[291 ]EPIMED Research Center, Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy

[292 ]Institute of Cellular Medicine, Newcastle University, Newcastle NE1 7RU, UK

[293 ]Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, D-85764 Munich, Germany

[294 ]Klinikum Grosshadern, D-81377 Munich, Germany

[295 ]Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany, D-85764 Neuherberg, Germany

[296 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA

[297 ]Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, 21589 Jeddah, Saudi Arabia

[298 ]Albert Einstein College of Medicine. Department of Epidemiology and Population Health, Belfer 1306, NY 10461, USA

[299 ]Division of Population Health Sciences & Education, St George’s, University of London, London SW17 0RE, UK

[300 ]Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

[301 ]Queensland Brain Institute, The University of Queensland, Brisbane 4072, Australia

[302 ]The University of Queensland Diamantina Institute, The Translation Research Institute, Brisbane 4012, Australia

[303 ]Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, OX3 7LJ, UK

[304 ]Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

[305 ]University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 OQQ, UK

[306 ]NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 OQQ, UK

[307 ]The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

[308 ]The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

[309 ]The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

[310 ]Department of Biostatistics, University of Liverpool, Liverpool L69 3GA, UK

Author notes

Correspondence and requests for materials should be addressed to K.L.M. ( mohlke@ 123456med.unc.edu ) or C.M.L. ( celi@ 123456well.ox.ac.uk )

[§]

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.

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Manuscript ID: EMS61357

DOI: 10.1038/nature14132

PMC ID: 4338562

PubMed ID: 25673412

SO-VID: 5db26dd8-381f-4590-a719-e37010ec8088

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

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