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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.

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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