Kuwait Medical Electronic Library

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

Valérie Turcot # 1, Yingchang Lu # 2 3 4, Heather M Highland # 5 6, Claudia Schurmann # 3 4, Anne E Justice # 5, Rebecca S Fine # 7 8 9, Jonathan P Bradfield 10 11, Tõnu Esko 7 9 12, Ayush Giri 13, Mariaelisa Graff 5, Xiuqing Guo 14, Audrey E Hendricks 15 16, Tugce Karaderi 17 18, Adelheid Lempradl 19, Adam E Locke 20 21, Anubha Mahajan 17, Eirini Marouli 22, Suthesh Sivapalaratnam 23 24 25, Kristin L Young 5, Tamuno Alfred 3, Mary F Feitosa 26, Nicholas G D Masca 27 28, Alisa K Manning 7 24 29 30, Carolina Medina-Gomez 31 32, Poorva Mudgal 33, Maggie C Y Ng 33 34, Alex P Reiner 35 36, Sailaja Vedantam 7 8 9, Sara M Willems 37, Thomas W Winkler 38, Gonçalo Abecasis 20, Katja K Aben 39 40, Dewan S Alam 41, Sameer E Alharthi 22 42, Matthew Allison 43, Philippe Amouyel 44 45 46, Folkert W Asselbergs 47 48 49, Paul L Auer 50, Beverley Balkau 51, Lia E Bang 52, Inês Barroso 15 53 54, Lisa Bastarache 55, Marianne Benn 56 57, Sven Bergmann 58 59, Lawrence F Bielak 60, Matthias Blüher 61 62, Michael Boehnke 20, Heiner Boeing 63, Eric Boerwinkle 64 65, Carsten A Böger 66, Jette Bork-Jensen 67, Michiel L Bots 68, Erwin P Bottinger 3, Donald W Bowden 33 34 69, Ivan Brandslund 70 71, Gerome Breen 72 73, Murray H Brilliant 74, Linda Broer 32, Marco Brumat 75, Amber A Burt 76, Adam S Butterworth 77 78, Peter T Campbell 79, Stefania Cappellani 80, David J Carey 81, Eulalia Catamo 80, Mark J Caulfield 22 82, John C Chambers 83 84 85, Daniel I Chasman 7 86 87 88, Yii-Der I Chen 14, Rajiv Chowdhury 77, Cramer Christensen 89, Audrey Y Chu 90 91, Massimiliano Cocca 92, Francis S Collins 93, James P Cook 94, Janie Corley 95 96, Jordi Corominas Galbany 97 98, Amanda J Cox 33 34 99, David S Crosslin 100, Gabriel Cuellar-Partida 101 102, Angela D'Eustacchio 80, John Danesh 15 77 78 103, Gail Davies 94 95, Paul I W Bakker 68 104, Mark C H Groot 105 106, Renée Mutsert 107, Ian J Deary 94 95, George Dedoussis 108, Ellen W Demerath 109, Martin Heijer 110, Anneke I Hollander 98, Hester M Ruijter 111, Joe G Dennis 112, Josh C Denny 55, Emanuele Di Angelantonio 77 78, Fotios Drenos 113 114, Mengmeng Du 36 115, Marie-Pierre Dubé 1 116, Alison M Dunning 117, Douglas F Easton 112 117, Todd L Edwards 13, David Ellinghaus 118, Patrick T Ellinor 7 24 30, Paul Elliott 119, Evangelos Evangelou 84 120, Aliki-Eleni Farmaki 108 121, I Sadaf Farooqi 53 54, Jessica D Faul 122, Sascha Fauser 123, Shuang Feng 20, Ele Ferrannini 124 125, Jean Ferrieres 126, Jose C Florez 7 24 29 30, Ian Ford 127, Myriam Fornage 128, Oscar H Franco 31, Andre Franke 118, Paul W Franks 129 130 131, Nele Friedrich 132, Ruth Frikke-Schmidt 57 133, Tessel E Galesloot 40, Wei Gan 17, Ilaria Gandin 134, Paolo Gasparini 75 80, Jane Gibson 135, Vilmantas Giedraitis 136, Anette P Gjesing 67, Penny Gordon-Larsen 137 138, Mathias Gorski 38 66, Hans-Jörgen Grabe 139 140, Struan F A Grant 10 141 142, Niels Grarup 67, Helen L Griffiths 143, Megan L Grove 64, Vilmundur Gudnason 144 145, Stefan Gustafsson 146, Jeff Haessler 36, Hakon Hakonarson 10 141, Anke R Hammerschlag 147, Torben Hansen 67, Kathleen Mullan Harris 137 148, Tamara B Harris 149, Andrew T Hattersley 150, Christian T Have 67, Caroline Hayward 151, Liang He 152 153, Nancy L Heard-Costa 90 154, Andrew C Heath 155, Iris M Heid 38 156, Øyvind Helgeland 157 158, Jussi Hernesniemi 159 160 161, Alex W Hewitt 162 163 164, Oddgeir L Holmen 165, G Kees Hovingh 23, Joanna M M Howson 77, Yao Hu 166, Paul L Huang 24, Jennifer E Huffman 151, M Arfan Ikram 31 167 168, Erik Ingelsson 146 169, Anne U Jackson 20, Jan-Håkan Jansson 170 171, Gail P Jarvik 76 172, Gorm B Jensen 173, Yucheng Jia 14, Stefan Johansson 158 174, Marit E Jørgensen 175 176, Torben Jørgensen 57 177 178, J Wouter Jukema 179 180, Bratati Kahali 181 182 183 184, René S Kahn 185, Mika Kähönen 186 187, Pia R Kamstrup 56, Stavroula Kanoni 22, Jaakko Kaprio 153 188 189, Maria Karaleftheri 190, Sharon L R Kardia 60, Fredrik Karpe 191 192, Sekar Kathiresan 7 24 88, Frank Kee 193, Lambertus A Kiemeney 40, Eric Kim 14, Hidetoshi Kitajima 17, Pirjo Komulainen 194 195 196, Jaspal S Kooner 83 85 197 198, Charles Kooperberg 36, Tellervo Korhonen 153 189 199, Peter Kovacs 61, Helena Kuivaniemi 81 200 201, Zoltán Kutalik 59 202, Kari Kuulasmaa 189, Johanna Kuusisto 203, Markku Laakso 203, Timo A Lakka 194 195 196, David Lamparter 58 59, Ethan M Lange 204, Leslie A Lange 204, Claudia Langenberg 37, Eric B Larson 76 205 206, Nanette R Lee 207 208, Terho Lehtimäki 160 161, Cora E Lewis 209, Huaixing Li 166, Jin Li 169, Ruifang Li-Gao 107, Honghuang Lin 210, Keng-Hung Lin 211, Li-An Lin 128, Xu Lin 166, Lars Lind 212, Jaana Lindström 189, Allan Linneberg 178 213 214, Ching-Ti Liu 215, Dajiang J Liu 216, Yongmei Liu 217, Ken S Lo 1, Artitaya Lophatananon 218, Andrew J Lotery 143, Anu Loukola 153 188, Jian'an Luan 37, Steven A Lubitz 7 24 30, Leo-Pekka Lyytikäinen 160 161, Satu Männistö 189, Gaëlle Marenne 15, Angela L Mazul 5, Mark I McCarthy 17 191 192, Roberta McKean-Cowdin 219, Sarah E Medland 102, Karina Meidtner 220 221, Lili Milani 12, Vanisha Mistry 53 54, Paul Mitchell 222, Karen L Mohlke 204, Leena Moilanen 223, Marie Moitry 224 225, Grant W Montgomery 102 226, Dennis O Mook-Kanamori 107 227, Carmel Moore 78 228, Trevor A Mori 229, Andrew D Morris 230, Andrew P Morris 17 94, Martina Müller-Nurasyid 156 231 232, Patricia B Munroe 22 82, Mike A Nalls 233 234, Narisu Narisu 93, Christopher P Nelson 27 28, Matt Neville 191 192, Sune F Nielsen 56 57, Kjell Nikus 159, Pål R Njølstad 157 158, Børge G Nordestgaard 56 57, Dale R Nyholt 102 235, Jeffrey R O'Connel 236, Michelle L O'Donoghue 237, Loes M Olde Loohuis 238, Roel A Ophoff 185 238, Katharine R Owen 191 192, Chris J Packard 127, Sandosh Padmanabhan 127, Colin N A Palmer 239, Nicholette D Palmer 69, Gerard Pasterkamp 111 240, Aniruddh P Patel 7 24 88, Alison Pattie 96, Oluf Pedersen 67, Peggy L Peissig 74, Gina M Peloso 215, Craig E Pennell 241, Markus Perola 12 188 189 242, James A Perry 236, John R B Perry 37, Tune H Pers 67 243, Thomas N Person 74, Annette Peters 221 232 244, Eva R B Petersen 245, Patricia A Peyser 60, Ailith Pirie 117, Ozren Polasek 230 246, Tinca J Polderman 147, Hannu Puolijoki 247, Olli T Raitakari 248 249, Asif Rasheed 250, Rainer Rauramaa 194 195, Dermot F Reilly 91, Frida Renström 129 251, Myriam Rheinberger 66, Paul M Ridker 87 88 237, John D Rioux 1 116, Manuel A Rivas 7 252, David J Roberts 78 253 254, Neil R Robertson 17 191, Antonietta Robino 80, Olov Rolandsson 170 255, Igor Rudan 230, Katherine S Ruth 256, Danish Saleheen 250 257, Veikko Salomaa 189, Nilesh J Samani 27 28, Yadav Sapkota 102, Naveed Sattar 127, Robert E Schoen 258, Pamela J Schreiner 109, Matthias B Schulze 220 221, Robert A Scott 37, Marcelo P Segura-Lepe 84, Svati H Shah 259, Wayne H-H Sheu 260 261 262, Xueling Sim 20 263, Andrew J Slater 264 265, Kerrin S Small 266, Albert V Smith 144 145, Lorraine Southam 15 17, Timothy D Spector 266, Elizabeth K Speliotes 181 182 183, John M Starr 95 267, Kari Stefansson 144 268, Valgerdur Steinthorsdottir 268, Kathleen E Stirrups 22 25, Konstantin Strauch 156 269, Heather M Stringham 20, Michael Stumvoll 61 62, Liang Sun 152 153, Praveen Surendran 77, Amy J Swift 93, Hayato Tada 237 270, Katherine E Tansey 114 271, Jean-Claude Tardif 1, Kent D Taylor 14, Alexander Teumer 272, Deborah J Thompson 112, Gudmar Thorleifsson 268, Unnur Thorsteinsdottir 144 268, Betina H Thuesen 178, Anke Tönjes 273, Gerard Tromp 81 201, Stella Trompet 179 274, Emmanouil Tsafantakis 275, Jaakko Tuomilehto 189 276 277 278, Anne Tybjaerg-Hansen 57 133, Jonathan P Tyrer 117, Rudolf Uher 279, André G Uitterlinden 31 32, Matti Uusitupa 280, Sander W Laan 111, Cornelia M Duijn 31, Nienke Leeuwen 281 282, Jessica van Setten 47, Mauno Vanhala 283 284, Anette Varbo 56 57, Tibor V Varga 129, Rohit Varma 285, Digna R Velez Edwards 286, Sita H Vermeulen 40, Giovanni Veronesi 287, Henrik Vestergaard 67 176, Veronique Vitart 151, Thomas F Vogt 288, Uwe Völker 289 290, Dragana Vuckovic 75 80, Lynne E Wagenknecht 217, Mark Walker 291, Lars Wallentin 292, Feijie Wang 166, Carol A Wang 241, Shuai Wang 215, Yiqin Wang 166, Erin B Ware 60 122, Nicholas J Wareham 37, Helen R Warren 22 82, Dawn M Waterworth 293, Jennifer Wessel 294, Harvey D White 295, Cristen J Willer 181 182 296, James G Wilson 297, Daniel R Witte 298 299, Andrew R Wood 256, Ying Wu 204, Hanieh Yaghootkar 256, Jie Yao 14, Pang Yao 166, Laura M Yerges-Armstrong 236 300, Robin Young 77 127, Eleftheria Zeggini 15, Xiaowei Zhan 301, Weihua Zhang 83 84, Jing Hua Zhao 37, Wei Zhao 257, Wei Zhao 60, Wei Zhou 181 182, Krina T Zondervan 17 302; CHD Exome+ Consortium; EPIC-CVD Consortium; ExomeBP Consortium; Global Lipids Genetic Consortium; GoT2D Genes Consortium; EPIC InterAct Consortium; INTERVAL Study; ReproGen Consortium; T2D-Genes Consortium; MAGIC Investigators; Understanding Society Scientific Group; Jerome I Rotter 14, John A Pospisilik 19, Fernando Rivadeneira 31 32, Ingrid B Borecki 26, Panos Deloukas 22 42, Timothy M Frayling 256, Guillaume Lettre 1 116, Kari E North 303, Cecilia M Lindgren 17 304, Joel N Hirschhorn 305 306 307 308, Ruth J F Loos 309 310 311

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Affiliations

1Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
2Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
3Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
6Human Genetics Center, University of Texas School of Public Health, University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
7Broad Institute of MIT and Harvard, Cambridge, MA, USA.
8Department of Genetics, Harvard Medical School, Boston, MA, USA.
9Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
10Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
11Quantinuum Research, LLC, San Diego, CA, USA.
12Estonian Genome Center, University of Tartu, Tartu, Estonia.
13Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
14Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA.
15Wellcome Trust Sanger Institute, Hinxton, UK.
16Department of Mathematical and Statistical Sciences, University of Colorado, Denver, CO, USA.
17Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
18Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus.
19Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
20Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
21McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
22William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
23Department of Vascular Medicine, AMC, Amsterdam, The Netherlands.
24Massachusetts General Hospital, Boston, MA, USA.
25Department of Haematology, University of Cambridge, Cambridge, UK.
26Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
27Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester, UK.
28NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
29Department of Medicine, Harvard Medical School, Boston, MA, USA.
30Medical and Population Genetics Program, Broad Institute, Cambridge, MA, USA.
31Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
32Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
33Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
34Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
35Department of Epidemiology, University of Washington, Seattle, WA, USA.
36Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
37MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.
38Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
39Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
40Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
41School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada.
42Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
43Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.
44INSERM U1167, Lille, France.
45Institut Pasteur de Lille, U1167, Lille, France.
46Université de Lille, U1167, RID-AGE, Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.
47Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
48Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
49Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
50Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
51INSERM U1018, Centre de Recherche en Épidémiologie et Santé des Populations (CESP), Villejuif, France.
52Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
53Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
54NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
55Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
56Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
57Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
58Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
59Swiss Institute of Bioinformatics, Lausanne, Switzerland.
60Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
61IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
62Department of Medicine, University of Leipzig, Leipzig, Germany.
63Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany.
64School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
65Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
66Department of Nephrology, University Hospital Regensburg, Regensburg, Germany.
67Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
68Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
69Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
70Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
71Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark.
72MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
73NIHR Biomedical Research Centre for Mental Health, South London and Maudsley Hospital, London, UK.
74Marshfield Clinic Research Institute, Marshfield, WI, USA.
75Department of Medical Sciences, University of Trieste, Trieste, Italy.
76Department of Medicine, University of Washington, Seattle, WA, USA.
77MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
78NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
79Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA.
80Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.
81Weis Center for Research, Geisinger Health System, Danville, PA, USA.
82NIHR Barts Cardiovascular Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
83Department of Cardiology, London North West Healthcare NHS Trust, Ealing Hospital, Middlesex, UK.
84Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
85Imperial College Healthcare NHS Trust, London, UK.
86Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
87Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
88Harvard Medical School, Boston, MA, USA.
89Medical Department, Lillebaelt Hospital, Vejle, Denmark.
90NHLBI Framingham Heart Study, Framingham, MA, USA.
91Genetics and Pharmacogenomics, Merck, Sharp & Dohme, Boston, MA, USA.
92Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
93Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA.
94Department of Biostatistics, University of Liverpool, Liverpool, UK.
95Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
96Department of Psychology, University of Edinburgh, Edinburgh, UK.
97Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
98Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
99Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia.
100Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA.
101Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia.
102QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
103British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK.
104Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
105Department of Clinical Chemistry and Haematology, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
106Utrecht Institute for Pharmaceutical Sciences, Division Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
107Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
108Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
109Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
110Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
111Laboratory of Experimental Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
112Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
113Institute of Cardiovascular Science, University College London, London, UK.
114MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, UK.
115Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
116Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
117Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
118Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
119Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
120Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
121Department of Health Sciences, University of Leicester, Leicester, UK.
122Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
123Department of Ophthalmology, University of Cologne, Cologne, Germany.
124CNR Institute of Clinical Physiology, Pisa, Italy.
125Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
126Toulouse University School of Medicine, Toulouse, France.
127University of Glasgow, Glasgow, UK.
128Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
129Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmo, Sweden.
130Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
131Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, Sweden.
132Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
133Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
134Research Unit, AREA Science Park, Trieste, Italy.
135Centre for Biological Sciences, Faculty of Natural and Environmental Sciences, University of Southampton, Southampton, UK.
136Geriatrics, Department of Public Health, Uppsala University, Uppsala, Sweden.
137Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
138Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
139Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
140German Center for Neurodegenerative Diseases (DZNE), Rostock/Greifswald, Greifswald, Germany.
141Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
142Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
143Vision Sciences, Clinical Neurosciences Research Group, Faculty of Medicine, University of Southampton, Southampton, UK.
144Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
145Icelandic Heart Association, Kopavogur, Iceland.
146Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
147Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, The Netherlands.
148Department of Sociology, University of North Carolina, Chapel Hill, NC, USA.
149Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, US National Institutes of Health, Bethesda, MD, USA.
150University of Exeter Medical School, University of Exeter, Exeter, UK.
151MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
152Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, USA.
153Department of Public Health, University of Helsinki, Helsinki, Finland.
154Department of Neurology, Boston University School of Medicine, Boston, MA, USA.
155Department of Psychiatry, Washington University, St. Louis, MO, USA.
156Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
157Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
158KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
159Department of Cardiology, Heart Center, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
160Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
161Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
162Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia.
163Centre for Ophthalmology and Vision Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.
164Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia.
165KG Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
166Key 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, China.
167Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands.
168Department of Radiology, Erasmus Medical Center, Rotterdam, The Netherlands.
169Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
170Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
171Research Unit Skellefteå, Skellefteå, Sweden.
172Department of Genome Sciences, University of Washington, Seattle, WA, USA.
173Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, Denmark.
174Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
175National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
176Steno Diabetes Center Copenhagen, Gentofte, Denmark.
177Faculty of Medicine, Aalborg University, Aalborg, Denmark.
178Research Center for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark.
179Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
180Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
181Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
182Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
183Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
184Centre for Brain Research, Indian Institute of Science, Bangalore, India.
185Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
186Department of Clinical Physiology, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
187Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
188Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
189National Institute for Health and Welfare, Helsinki, Finland.
190Echinos Medical Centre, Echinos, Greece.
191Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
192Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK.
193UKCRC Centre of Excellence for Public Health Research, Queens University Belfast, Belfast, UK.
194Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland.
195Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
196Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
197National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, UK.
198MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
199Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
200Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
201Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
202Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.
203Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
204Department of Genetics, University of North Carolina, Chapel Hill, NC, USA.
205Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
206Department of Health Services, University of Washington, Seattle, WA, USA.
207Department of Anthropology, Sociology and History, University of San Carlos, Cebu City, Philippines.
208USC-Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines.
209Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
210Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
211Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan.
212Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
213Department of Clinical Experimental Research, Rigshospitalet, Copenhagen, Denmark.
214Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
215Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
216Department of Public Health Sciences, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
217Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
218Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK.
219Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
220Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Nuthetal, Germany.
221German Center for Diabetes Research, Neuherberg, Germany.
222Westmead Millennium Institute of Medical Research, Centre for Vision Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, Australia.
223Department of Medicine, Kuopio University Hospital, Kuopio, Finland.
224Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France.
225Department of Public Health, University Hospital of Strasbourg, Strasbourg, France.
226Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
227Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
228INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
229School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
230Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
231Department of Medicine I, University Hospital Großhadern, Ludwig-Maximilians-Universitat, Munich, Germany.
232German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
233Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, MD, USA.
234Data Tecnica International, Glen Echo, MD, USA.
235Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
236Program for Personalized and Genomic Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
237Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
238Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
239Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, UK.
240Laboratory of Clinical Chemistry and Hematology, Division of Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
241School of Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
242Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.
243Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
244Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
245Department of Clinical Immunology and Biochemistry, Lillebaelt Hospital, Vejle, Denmark.
246School of Medicine, University of Split, Split, Croatia.
247Central Hospital of Southern Ostrobothnia, Seinäjoki, Finland.
248Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
249Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
250Centre for Non-Communicable Diseases, Karachi, Pakistan.
251Department of Biobank Research, Umeå University, Umeå, Sweden.
252Wellcome Trust Centre for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
253NHS Blood and Transplant-Oxford Centre, Oxford, UK.
254BRC Haematology Theme and Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
255Department of Public Health and Clinical Medicine, Unit of Family Medicine, Umeå University, Umeå, Sweden.
256Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.
257Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
258Departments of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
259Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
260Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
261School of Medicine, National Defense Medical Center, Taipei, Taiwan.
262School of Medicine, National Yang-Ming University, Taipei, Taiwan.
263Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore, Singapore.
264Genetics, Target Sciences, GlaxoSmithKline, Research Triangle Park, NC, USA.
265OmicSoft at Qiagen Company, Cary, NC, USA.
266Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
267Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
268deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
269Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
270Kanazawa University, Kanazawa, Japan.
271College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK.
272Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
273Center for Pediatric Research, Department for Women's and Child Health, University of Leipzig, Leipzig, Germany.
274Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
275Anogia Medical Centre, Anogia, Greece.
276Centre for Vascular Prevention, Danube University Krems, Krems, Austria.
277Dasman Diabetes Institute, Dasman, Kuwait.
278Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
279Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
280Department of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
281Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
282Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
283Primary Health Care Unit, Central Hospital of Central Finland, Jyväskylä, Finland.
284Primary Health Care Unit, Kuopio University Hospital, Kuopio, Finland.
285USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
286Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
287Research Center on Epidemiology and Preventive Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy.
288Cardiometabolic Disease, Merck, Sharp & Dohme, Kenilworth, NJ, USA.
289German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany.
290Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
291Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle, UK.
292Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
293Genetics, Target Sciences, GlaxoSmithKline, King of Prussia, PA, USA.
294Departments of Epidemiology and Medicine, Diabetes Translational Research Center, Fairbanks School of Public Health and School of Medicine, Indiana University, Indianapolis, IN, USA.
295Green Lane Cardiovascular Service, Auckland City Hospital and University of Auckland, Auckland, New Zealand.
296Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
297Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
298Danish Diabetes Academy, Odense, Denmark.
299Department of Public Health, Aarhus University, Aarhus, Denmark.
300GlaxoSmithKline, King of Prussia, PA, USA.
301Department of Clinical Sciences, Quantitative Biomedical Research Center, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA.
302Endometriosis CaRe Centre, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
303Department of Epidemiology and Carolina Center of Genome Sciences, Chapel Hill, NC, USA.
304Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, University of Oxford, Oxford, UK.
305Broad Institute of MIT and Harvard, Cambridge, MA, USA. joelh@broadinstitute.org.
306Department of Genetics, Harvard Medical School, Boston, MA, USA. joelh@broadinstitute.org.
307Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA. joelh@broadinstitute.org.
308Department of Pediatrics, Harvard Medical School, Boston, MA, USA. joelh@broadinstitute.org.
309Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@mssm.edu.
310Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@mssm.edu.
311Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ruth.loos@mssm.edu.

01 January 2018

doi: 10.1038/s41588-017-0011-x

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, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

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

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