Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity

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Abstract

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes ( ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two ( MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity.

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Most cited references 112

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Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. We describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of truncating variants with 72% having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human “knockout” variants in protein-coding genes.

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METAL: fast and efficient meta-analysis of genomewide association scans

Cristen Willer, Yun Li, Gonçalo R Abecasis (2010)

Summary: METAL provides a computationally efficient tool for meta-analysis of genome-wide association scans, which is a commonly used approach for improving power complex traits gene mapping studies. METAL provides a rich scripting interface and implements efficient memory management to allow analyses of very large data sets and to support a variety of input file formats. Availability and implementation: METAL, including source code, documentation, examples, and executables, is available at http://www.sph.umich.edu/csg/abecasis/metal/ Contact: goncalo@umich.edu

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Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues. Copyright © 2015, American Association for the Advancement of Science.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 4 May 2018

Publication date (Electronic): 22 December 2017

Publication date (Print): January 2018

Publication date PMC-release: 22 June 2018

Volume: 50

Issue: 1

Pages: 26-41

Affiliations

[1 ]Montreal Heart Institute, Universite de Montreal, Montreal, Quebec, H1T 1C8, Canada

[2 ]Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, 37203, USA

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

[4 ]The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, 10069, USA

[5 ]Department of Epidemiology, University of North Carolina, Chapel Hill, NC, 27514, USA

[6 ]Human Genetics Center, The University of Texas School of Public Health, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

[7 ]Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA

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

[9 ]Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, 02115, USA

[10 ]Center for Applied Genomics, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA

[11 ]Quantinuum Research LLC, San Diego CA, 92101, USA

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

[13 ]Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, 37203, USA

[14 ]Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, 90502, USA

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

[16 ]Department of Mathematical and Statistical Sciences, University of Colorado, Denver, CO, 80204, USA

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

[18 ]Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus

[19 ]Max Planck Institute of Immunobiology and Epigenetics, Freiburg, 79108, Germany

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

[21 ]McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, 63108, USA

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

[23 ]Department of Vascular Medicine, AMC, Amsterdam, 1105 AZ, The Netherlands

[24 ]Massachusetts General Hospital, Boston, MA, 02114, USA

[25 ]Department of Haematology, University of Cambridge, Cambridge, CB2 0PT, UK

[26 ]Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63108, USA

[27 ]Department of Cardiovascular Sciences, Univeristy of Leicester, Glenfield Hospital, Leicester, LE3 9QP, UK

[28 ]NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK

[29 ]Department of Medicine, Harvard University Medical School, Boston, MA, 02115, USA

[30 ]Medical and Population Genetics Program, Broad Institute, Cambridge, MA, 02141, USA

[31 ]Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands

[32 ]Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands

[33 ]Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

[34 ]Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

[35 ]Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA

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

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

[38 ]Department of Genetic Epidemiology, University of Regensburg, Regensburg, D-93051, Germany

[39 ]Netherlands Comprehensive Cancer Organisation, Utrecht, 3501 DB, The Netherlands

[40 ]Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands

[41 ]School of Kinesiology and Health Science, Faculty of Health, York University, Toronto

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

[43 ]Department of Family Medicine & Public Health, University of California, San Diego, La Jolla, CA, 92093, USA

[44 ]INSERM U1167, Lille, F-59019, France

[45 ]Institut Pasteur de Lille, U1167, Lille, F-59019, France

[46 ]Universite de Lille, U1167 - RID-AGE - Risk factors and molecular determinants of aging-related diseases, Lille, F-59019, France

[47 ]Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands

[48 ]Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands

[49 ]Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK

[50 ]Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, 53201, USA

[51 ]INSERM U1018, Centre de recherche en Épidemiologie et Sante des Populations (CESP), Villejuif, France

[52 ]Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark

[53 ]Metabolic Research Laboratories, University of Cambridge, Cambridge, CB2 0QQ, UK

[54 ]NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK

[55 ]Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, 37203, USA

[56 ]Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark

[57 ]Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark

[58 ]Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland

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

[60 ]Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, 48109, USA

[61 ]IFB Adiposity Diseases, University of Leipzig, Leipzig, 04103, Germany

[62 ]University of Leipzig, Department of Medicine, Leipzig, 04103, Germany

[63 ]Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany

[64 ]School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

[65 ]Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030 USA

[66 ]Department of Nephrology, University Hospital Regensburg, Regensburg, 93042, Germany

[67 ]The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark

[68 ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

[69 ]Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

[70 ]Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, 7100, Denmark

[71 ]Institute of Regional Health Research, University of Southern Denmark, Odense, 5000, Denmark

[72 ]MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, SE5 8AF, UK

[73 ]NIHR Biomedical Research Centre for Mental Health, South London and Maudsley Hospital, London, BR3 3BX, UK

[74 ]Marshfield Clinic Research Institute, Marshfield, WI, 54449, USA

[75 ]Department of Medical Sciences, University of Trieste, Trieste, 34137, Italy

[76 ]Department of Medicine, University of Washington, Seattle, WA, 98195, USA

[77 ]MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK

[78 ]NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK

[79 ]American Cancer Society, Epidemiology Research Program, Atlanta, GA, 30303, USA

[80 ]Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, 34137, Italy

[81 ]Weis Center for Research, Geisinger Health System, Danville, PA 17822

[82 ]NIHR Barts Cardiovascular Research Unit, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK

[83 ]Department of Cardiology, London North West Healthcare NHS Trust, Ealing Hospital, Middlesex, UB1 3HW, UK

[84 ]Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, W2 1PG, UK

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

[86 ]Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA

[87 ]Division of Preventive Medicine, Brigham and Women's and Harvard Medical School, Boston, MA, 02215, USA

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

[89 ]Medical department, Lillebaelt Hospital, Vejle, 7100, Denmark

[90 ]NHLBI Framingham Heart Study, Framingham, MA, 01702, USA

[91 ]Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, 34100, Italy

[92 ]Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA

[93 ]Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK

[94 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, EH8 9JZ, UK

[95 ]Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK

[96 ]Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands

[97 ]Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands

[98 ]Menzies Health Institute Queensland, Griffith University, Southport, QLD, Australia

[99 ]Department of Biomedical Infomatics and Medical Education, University of Washington, Seattle, WA, 98195, USA

[100 ]Diamantina Institute, University of Queensland, Brisbane, Queensland, 4072, Australia

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

[102 ]British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK

[103 ]Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

[104 ]Department of Clinical Chemistry and Haematology, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, 3508 GA, The Netherlands

[105 ]Utrecht Institute for Pharmaceutical Sciences, Division Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, 3508 TB, The Netherlands

[106 ]Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands

[107 ]Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, 17671, Greece

[108 ]Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, 55454, USA

[109 ]VU University Medical Center, Department of Internal Medicine, Amsterdam, 1007 MB, The Netherlands

[110 ]Laboratory of Experimental Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

[111 ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK

[112 ]Institute of Cardiovascular Science, University College London, London, WC1E 6JF, UK

[113 ]MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, BS8 2BN, UK

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

[115 ]Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY, 10017, USA

[116 ]Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, H3T 1J4, Canada

[117 ]Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK

[118 ]Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany

[119 ]Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK

[120 ]Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece

[121 ]Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK

[122 ]Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA

[123 ]Department of Ophthalmology, University of Cologne, Cologne, 50937, Germany

[124 ]CNR Institute of Clinical Physiology, Pisa, Italy

[125 ]Department of Clinical & Experimental Medicine, University of Pisa, Italy

[126 ]Toulouse University School of Medicine, Toulouse, TSA 50032 31059, France

[127 ]University of Glasgow, Glasgow, G12 8QQ, UK

[128 ]Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA

[129 ]Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmo, SE-20502, Sweden

[130 ]Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA

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

[132 ]Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, 17475, Germany

[133 ]Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark

[134 ]Ilaria Gandin, Research Unit, AREA Science Park, Trieste, 34149, Italy

[135 ]Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy

[136 ]Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, SO17 1BJ, UK

[137 ]Geriatrics, Department of Public Health, Uppsala University, Uppsala, 751 85, Sweden

[138 ]Carolina Population Center, University of North Carolina, Chapel Hill, NC, 27514, USA

[139 ]Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27514, USA

[140 ]Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, 17475, Germany

[141 ]German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Greifswald, 17475, Germany

[142 ]Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

[143 ]Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA

[144 ]Vision Sciences, Clinical Neurosciences Research Group, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK

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

[146 ]Icelandic Heart Association, Kopavogur, 201, Iceland

[147 ]Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, 751 41, Sweden

[148 ]Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, 1081 HV, The Netherlands

[149 ]Department of Sociology, University of North Carolina, Chapel Hill, NC, 27514, USA

[150 ]Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, MD, 20892, USA

[151 ]University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK

[152 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK

[153 ]Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708, USA

[154 ]Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland

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

[156 ]Department of Psychiatry, Washington University, Saint Louis, MO, 63110, USA

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

[158 ]Department of Pediatrics, Haukeland University Hospital, Bergen, 5021, Norway

[159 ]KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, 5020, Norway

[160 ]Department of Cardiology, Heart Center, Tampere University Hospital, and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33521, Finland

[161 ]Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33521, Finland

[162 ]Department of Clinical Chemistry, Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland

[163 ]Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, 3002, Australia

[164 ]Centre for Ophthalmology and Vision Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, 6009, Australia

[165 ]Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, 7000, Australia

[166 ]K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, 7600, Norway

[167 ]AMC, Department of Vascular Medicine, Amsterdam, 1105 AZ, The Netherlands

[168 ]Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People's Republic of China, Shanghai, 200031, China

[169 ]Department of Neurology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands

[170 ]Department of Radiology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands

[171 ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 943 05, USA

[172 ]Department of Public Health & Clinical Medicine, Umeå University, Umeå, SE-90185, Sweden

[173 ]Research Unit Skellefteå, Skellefteå, SE-93141, Sweden

[174 ]Department of Genome Sciences, University of Washington, Seattle, WA, 98195, USA

[175 ]The Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, 2000, Denmark

[176 ]Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, 5021, Norway

[177 ]National Institute of Public Health, University of Southern Denmark, Copenhagen, 1353, Denmark

[178 ]Steno Diabetes Center Copenhagen, Gentofte, 2800, Denmark

[179 ]Faculty of medicine, Aalborg University, Aalborg, DK-9000, Denmark

[180 ]Research Center for Prevention and Health, Capital Region of Denmark, Glostrup, DK-2600, Denmark

[181 ]Department of Cardiology, Leiden University Medical Center, Leiden, 2333, The Netherlands

[182 ]The Interuniversity Cardiology Institute of the Netherlands, Utrecht, 2333, The Netherlands

[183 ]Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA

[184 ]Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA

[185 ]Division of Gastroenterology, University of Michigan, Ann Arbor, MI, 48109, USA

[186 ]Centre for Brain Research, Indian Institute of Science, Bangalore 560012, India

[187 ]Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands

[188 ]Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland

[189 ]Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland

[190 ]Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, FI-00014, Finland

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

[192 ]Echinos Medical Centre, Echinos, Greece

[193 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK

[194 ]Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, OX3 7LE, UK

[195 ]UKCRC Centre of Excellence for Public Health Research, Queens University Belfast, Belfast, UK, BT12 6BJ, UK

[196 ]Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland

[197 ]Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, 70210, Finland

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

[199 ]National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK

[200 ]MRC-PHE Centre for Environment and Health, Imperial College London, London, W2 1PG, UK

[201 ]University of Eastern Finland, Kuopio, 70210, Finland

[202 ]University of Helsinki, Helsinki, 00100, Finland

[203 ]Department of Psychiatry, and Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Western Cape, 7505, South Africa

[204 ]Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland

[205 ]Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, 70210, Finland

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

[207 ]Kaiser Permanente Washington Health Research Institute Seattle WA 98101

[208 ]Department of Health Services, University of Washington, Seattle WA 98101

[209 ]Department of Anthropology, Sociology, and History, University of San Carlos, Cebu City, 6000, Philippines

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

[211 ]Division of Preventive Medicine University of Alabama at Birmingham, Birmingham, AL 35205, USA

[212 ]Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, 94304, USA

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

[214 ]Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan 407, Taiwan

[215 ]Uppsala University, Uppsala, 75185, Sweden

[216 ]Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, DK-2200, Denmark

[217 ]Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark

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

[219 ]Department of Public Health Sciences, Institute for Personalized Medicine, the Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

[220 ]Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

[221 ]Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, CV4 7AL, UK

[222 ]Department of Preventive Medicine, Keck School of Medicine of the University of California, Los Angeles, CA, 90089, USA

[223 ]Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany

[224 ]German Center for Diabetes Research, München-Neuherberg, 85764, Germany

[225 ]Westmead Millennium Institute of Medical Research, Centre for Vision Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, 2022, Australia

[226 ]Department of Medicine, Kuopio University Hospital, Kuopio, 70210, Finland

[227 ]Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, F-67085, France

[228 ]Department of Public Health, University Hospital of Strasbourg, Strasbourg, F-67081, France

[229 ]Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, 4072, Australia

[230 ]Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300RC, The Netherlands

[231 ]INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK

[232 ]School of Medicine and Pharmacology, The University of Western Australia, Perth, Western Australia, 6009, Australia

[233 ]Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9AG, UK

[234 ]Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universitat, Munich, 81377, Germany

[235 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, 80802, Germany

[236 ]Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, 20892, USA

[237 ]data tecnica international, Glen Echo, MD, USA

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

[239 ]Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, US

[240 ]Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA

[241 ]Center for Neurobehavioral Genetics, UCLA, Los Angeles, CA, 90095, USA

[242 ]Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK

[243 ]Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

[244 ]School of Women’s and Infants’ Health, The University of Western Australia, Perth, Western Australia, 6009, Australia

[245 ]University of Helsinki, Institute for Molecular Medicine (FIMM) and Diabetes and Obesity Research Program, Helsinki, FI00014, Finland

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

[247 ]Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2200, Denmark

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

[249 ]Department of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Vejle, 7100, Denmark

[250 ]School of Medicine, University of Split, Split, 21000, Croatia

[251 ]South Ostrobothnia Central Hospital, Seinajoki, 60220, Finland

[252 ]Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland

[253 ]Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20520, Finland

[254 ]Centre for Non-Communicable Diseases, Karachi, Pakistan

[255 ]Merck, Sharp & Dohme, Genetics and Pharmacogenomics, Boston, MA, 02115, USA

[256 ]Department of Biobank Research, Umeå University, Umeå, SE-90187, Sweden

[257 ]Nuffield Department of Clinical Medicine, Oxford, OX37 BN, UK

[258 ]NHS Blood and Transplant - Oxford Centre, Oxford, OX3 9BQ, UK

[259 ]BRC Haematology Theme and Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK

[260 ]Department of Public Health and Clinical Medicine, Unit of Family Medicine, Umeå University, Umeå, 90185, Sweden

[261 ]Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK

[262 ]Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

[263 ]University of Pittsburgh Medical Center, Departments of Medicine and Epidemiology, Pittsburgh, PA, 15213, USA

[264 ]Division of Epidemiology & Community Health University of Minnesota, Minneapolis, MN, 55454, USA

[265 ]Duke Molecular Physiology Institute, Duke University, Durham NC, 27701

[266 ]Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan 407, Taiwan

[267 ]School of Medicine, National Defense Medical Center, Taipei, Taiwan 114, Taiwan

[268 ]School of Medicine, National Yang-Ming University, Taipei, Taiwan

[269 ]Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore 117549, Singapore

[270 ]Genetics, Target Sciences, GlaxoSmithKline, Research Triangle Park, NC, 27709, US

[271 ]OmicSoft a QIAGEN Company, Cary, NC, 27513, US

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

[273 ]Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK

[274 ]deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland

[275 ]Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, 81377, Germany

[276 ]Kanazawa University, Kanazawa, 920-8641, Japan

[277 ]College of Biomedical and Life Sciences, Cardiff University, Cardiff, CF14 4EP, UK

[278 ]Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany

[279 ]Center for Pediatric Research, Department for Women's and Child Health, University of Leipzig, Leipzig, 04103, Germany

[280 ]Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Western Cape, 7505, South Africa

[281 ]Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2333, The Netherlands

[282 ]Anogia Medical Centre, Anogia, Greece

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

[284 ]Dasman Diabetes Institute, Dasman, 15462, Kuwait

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

[286 ]Department of Psychiatry, Dalhousie University, Halifax, B3H 4R2, Canada

[287 ]Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, 70210, Finland

[288 ]Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, 1081BT, The Netherlands

[289 ]Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands

[290 ]Central Finland Central Hospital, Jyvaskyla, 40620, Finland

[291 ]USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, 90033, USA

[292 ]Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, 37203, USA

[293 ]Research Center on Epidemiology and Preventive Medicine, Department of Medicine and Surgery, University of Insubria, Varese, 21100, Italy

[294 ]Merck, Sharp & Dohme, Cardiometabolic Disease, Kenilworth, NJ, 07033, USA

[295 ]DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, 17475, Germany

[296 ]Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17475, Germany

[297 ]Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, NE2 4HH, UK

[298 ]Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala, 752 37, Sweden

[299 ]Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, 48104, USA

[300 ]Genetics, Target Sciences, GlaxoSmithKline, King of Prussia, PA, US

[301 ]Departments of Epidemiology & Medicine, Diabetes Translational Research Center, Fairbanks School of Public Health & School of Medicine, Indiana University, Indiana, IN, 46202, USA

[302 ]Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland, New Zealand

[303 ]Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA

[304 ]Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA

[305 ]Danish Diabetes Academy, Odense, 5000, Denmark

[306 ]Department of Public Health, Aarhus University, Aarhus, 8000, Denmark

[307 ]GlaxoSmithKline, King of Prussia, PA, 19406, USA

[308 ]Department of Clinical Sciences, Quantitative Biomedical Research Center, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

[309 ]Endometriosis CaRe Centre, Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, OX3 9DU, UK

[310 ]Department of Epidemiology and Carolina Center of Genome Sciences, Chapel Hill, NC, 27514, USA

[311 ]Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford, OX3 7BN, UK

[312 ]Departments of Pediatrics and Genetics, Harvard Medical School, Boston, MA, 02115, USA

[313 ]The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10069, USA

Author notes

Correspondence to: Ruth J. F. Loos ( ruth.loos@ 123456mssm.edu ), Joel N. Hirschhorn ( joelh@ 123456broadinstitute.org )

[*]

These authors contributed equally to this work.

[§]

These authors jointly supervised this work.

Article

Manuscript ID: NIHMS920811

DOI: 10.1038/s41588-017-0011-x

PMC ID: 5945951

PubMed ID: 29273807

SO-VID: 851784f6-64a6-4307-b7b9-189970c16f4b

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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity

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