Nat Genet. 2018 Jan;50(1):26-41. doi: 10.1038/s41588-017-0011-x. Epub 2017 Dec 22.

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

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Author information

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

Erratum in

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.