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Nature. 2017 Feb 9;542(7640):186-190. doi: 10.1038/nature21039. Epub 2017 Feb 1.

Rare and low-frequency coding variants alter human adult height.

Marouli E1, Graff M2, Medina-Gomez C3,4, Lo KS5, Wood AR6, Kjaer TR7, Fine RS8,9,10, Lu Y11,12,13, Schurmann C12,13, Highland HM2,14, Rüeger S15,16, Thorleifsson G17, Justice AE2, Lamparter D16,18, Stirrups KE1,19, Turcot V5, Young KL2, Winkler TW20, Esko T8,10,21, Karaderi T22, Locke AE23,24, Masca NG25,26, Ng MC27,28, Mudgal P27, Rivas MA8,29, Vedantam S8,9,10, Mahajan A22, Guo X30, Abecasis G23, Aben KK31,32, Adair LS33, Alam DS34, Albrecht E35, Allin KH36, Allison M37, Amouyel P38,39,40, Appel EV36, Arveiler D41,42, Asselbergs FW43,44,45, Auer PL46, Balkau B47, Banas B48, Bang LE49, Benn M50,51, Bergmann S16,18, Bielak LF52, Blüher M53,54, Boeing H55, Boerwinkle E56,57, Böger CA48, Bonnycastle LL58, Bork-Jensen J36, Bots ML59, Bottinger EP12, Bowden DW27,28,60, Brandslund I61,62, Breen G63, Brilliant MH64, Broer L4, Burt AA65, Butterworth AS66,67, Carey DJ68, Caulfield MJ1,69, Chambers JC70,71,72, Chasman DI8,73,74,75, Chen YI30, Chowdhury R66, Christensen C76, Chu AY74,77, Cocca 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Lin H201, Lin LA118, Lin X199, Lind L202, Lindström J165, Linneberg A51,164,203, Liu Y30, Liu Y204, Lophatananon A205, Luan J192, Lubitz SA106,107, Lyytikäinen LP141,142, Mackey DA144, Madden PA206, Manning AK106,107,116, Männistö S165, Marenne G86, Marten J134, Martin NG85, Mazul AL2, Meidtner K182,207, Metspalu A21, Mitchell P208, Mohlke KL190, Mook-Kanamori DO93,209, Morgan A123, Morris AD210, Morris AP22,79, Müller-Nurasyid M35,211,212, Munroe PB1,69, Nalls MA213, Nauck M214,215, Nelson CP25,26, Neville M174,175, Nielsen SF50,51, Nikus K216, Njølstad PR138,139, Nordestgaard BG50,51, Ntalla I1, O'Connel JR217, Oksa H218, Loohuis LM219, Ophoff RA171,219, Owen KR174,175, Packard CJ117, Padmanabhan S117, Palmer CN220, Pasterkamp G221,222, Patel AP8,75,106, Pattie A81, Pedersen O36, Peissig PL64, Peloso GM106,107, Pennell CE223, Perola M165,224,225, Perry JA217, Perry JR192, Person TN64, Pirie A102, Polasek O210,226, Posthuma D227,228, Raitakari OT229,230, Rasheed A231, Rauramaa 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TV119, Varma R159, Edwards DR262, Vermeulen SH32, Vestergaard H36, Vitart V134, Vogt TF263, Vozzi D124, Walker M264, Wang F199, Wang CA223, Wang S265, Wang Y199, Wareham NJ192, Warren HR1,69, Wessel J266, Willems SM192, Wilson JG267, Witte DR268,269, Woods MO270, Wu Y190, Yaghootkar H6, Yao J30, Yao P199, Yerges-Armstrong LM217,271, Young R66,117, Zeggini E86, Zhan X272, Zhang W70,71, Zhao JH192, Zhao W239, Zhao W52, Zheng H199, Zhou W168,169; EPIC-InterAct Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium; MAGIC Investigators, Rotter JI30, Boehnke M23, Kathiresan S8,75,106, McCarthy MI22,174,175, Willer CJ168,169,273, Stefansson K17,128, Borecki IB111, Liu DJ274, North KE275, Heard-Costa NL77,276, Pers TH36,277, Lindgren CM22,278, Oxvig C7, Kutalik Z15,16, Rivadeneira F3,4, Loos RJ12,13,279, Frayling TM6, Hirschhorn JN8,10,280, Deloukas P1,281, Lettre G5,237.

Author information

1
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
2
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27514, USA.
3
Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands.
4
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands.
5
Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
6
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
7
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, 8000, Denmark.
8
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
9
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
10
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
11
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
12
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
13
The Genetics of Obesity and Related Metabolic Traits Program, Ichan School of Medicine at Mount Sinai, New York, New York 10069, USA.
14
Human Genetics Center, The University of Texas School of Public Health, The University of Texas Graduate School of Biomedical Sciences at Houston, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
15
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland.
16
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland.
17
deCODE Genetics/Amgen inc., Reykjavik, 101, Iceland.
18
Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland.
19
Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK.
20
Department of Genetic Epidemiology, University of Regensburg, Regensburg, D-93051, Germany.
21
Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
22
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
23
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
24
McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri 63108, USA.
25
Department of Cardiovascular Sciences, Univeristy of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.
26
NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
27
Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
28
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
29
Nuffield Department of Clinical Medicine, Oxford OX3 7BN, UK.
30
Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
31
Netherlands Comprehensive Cancer Organisation, Utrecht, 3501 DB, The Netherlands.
32
Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
33
Department of Nutrition, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
34
Centre for Control of Chronic Diseases (CCCD), Dhaka, 1212, Bangladesh.
35
Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
36
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark.
37
Department of Family Medicine &Public Health, University of California, San Diego, La Jolla, California 92093, USA.
38
INSERM U1167, Lille, F-59019, France.
39
Institut Pasteur de Lille, U1167, Lille, F-59019, France.
40
Universite de Lille, U1167 - RID-AGE - Risk factors and molecular determinants of aging-related diseases, Lille, F-59019, France.
41
Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, F-67085, France.
42
Department of Public Health, University Hospital of Strasbourg, Strasbourg, 67081, France.
43
Department of Cardiology, Division Heart &Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
44
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
45
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
46
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, USA.
47
INSERM U1018, Centre de recherche en Épidemiologie et Sante des Populations (CESP), Villejuif, France.
48
Department of Nephrology, University Hospital Regensburg, Regensburg, 93042, Germany.
49
Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.
50
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2730, Denmark.
51
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
52
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.
53
IFB Adiposity Diseases, University of Leipzig, Leipzig, 04103, Germany.
54
University of Leipzig, Department of Medicine, Leipzig, 04103, Germany.
55
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany.
56
School of Public Health, Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
57
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
58
Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
59
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
60
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
61
Department of Clinical Biochemistry, Lillebaelt Hospital, Vejle, 7100, Denmark.
62
Institute of Regional Health Research, University of Southern Denmark, Odense, 5000, Denmark.
63
MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London &NIHR Biomedical Research Centre for Mental Health at the Maudsley, London, SE5 8AF, UK.
64
Marshfield Clinic Research Foundation, Marshfield, Wisconsin 54449, USA.
65
Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
66
MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
67
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB1 8RN, UK.
68
The Sigfried and Janet Weis Center for Research, Danville, Pennsylvania 17822, USA.
69
NIHR Barts Cardiovascular Research Unit, Barts and The London School of Medicine &Dentistry, Queen Mary University, London EC1M 6BQ, UK.
70
Department of Cardiology, London North West Healthcare NHS Trust, Ealing Hospital, Middlesex UB1 3HW, UK.
71
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London W2 1PG, UK.
72
Imperial College Healthcare NHS Trust, London W12 0HS, UK.
73
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
74
Division of Preventive Medicine, Brigham and Women's and Harvard Medical School, Boston, Massachusetts 02215, USA.
75
Harvard Medical School, Boston, Massachusetts 02115, USA.
76
Medical Department, Lillebaelt Hospital, Vejle, 7100, Denmark.
77
NHLBI Framingham Heart Study, Framingham, Massachusetts 01702, USA.
78
Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, 34100, Italy.
79
Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
80
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
81
Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
82
Department of Human Genetics, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
83
Menzies Health Institute Queensland, Griffith University, Southport, Queensland, Australia.
84
Diamantina Institute, University of Qeensland, Brisbane, Queensland, 4072, Australia.
85
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia.
86
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
87
British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
88
Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
89
Department of Vascular Surgery, Division of Surgical Specialties, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
90
Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada.
91
Department of Clinical Chemistry and Haematology, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, 3508 GA, The Netherlands.
92
Utrecht Institute for Pharmaceutical Sciences, Division Pharmacoepidemiology &Clinical Pharmacology, Utrecht University, Utrecht, 3508 TB, The Netherlands.
93
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
94
Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, 17671, Greece.
95
Division of Epidemiology &Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55454, USA.
96
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands.
97
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
98
Institute of Cardiovascular Science, University College London, London WC1E 6JF, UK.
99
MRC Integrative Epidemiology Unit, School of Social &Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
100
Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, Washington 98109, USA.
101
Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, New York 10017, USA.
102
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
103
Department of Medicine, Oulu University Hospital, Oulu, 90029, Finland.
104
Research Unit of Internal Medicine, University of Oulu, Oulu, FI-90014, Finland.
105
Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee 37203, USA.
106
Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
107
Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts 02141, USA.
108
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
109
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, 45110, Greece.
110
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan 48104, USA.
111
Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, StLouis, Missouri 63108, USA.
112
CNR Institute of Clinical Physiology, Pisa, Italy.
113
Department of Clinical &Experimental Medicine, University of Pisa, Pisa, Italy.
114
Research Center on Epidemiology and Preventive Medicine, Department of Clinical and Experimental Medicine, University of Insubria, Varese, 21100, Italy.
115
Toulouse University School of Medicine, Toulouse, TSA 50032 31059, France.
116
Department of Medicine, Harvard University Medical School, Boston, Massachusetts 02115, USA.
117
University of Glasgow, Glasgow G12 8QQ, UK.
118
Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
119
Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, SE-20502, Sweden.
120
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
121
Department of Public Health and Clinical Medicine, Unit of Medicine, Umeå University, Umeå, 901 87, Sweden.
122
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, 2100, Denmark.
123
Department of Medical Sciences, University of Trieste, Trieste, 34137, Italy.
124
Division of Experimental Genetics, Sidra Medical and Research Center, Doha, 26999, Qatar.
125
Geriatrics, Department of Public Health, Uppsala University, Uppsala, 751 85, Sweden.
126
Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina 27514, USA.
127
Department of Nutrition, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina 27514, USA.
128
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
129
Icelandic Heart Association, Kopavogur, 201, Iceland.
130
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, 751 41, Sweden.
131
Department of Sociology, University of North Carolina, Chapel Hill, North Carolina 27514, USA.
132
Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
133
University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.
134
MRCHGU, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
135
Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, North Carolina 27708, USA.
136
Department of Public Health, University of Helsinki, Helsinki, FI-00014, Finland.
137
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, FI-00014, Finland.
138
Department of Pediatrics, Haukeland University Hospital, Bergen, 5021, Norway.
139
KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, 5020, Norway.
140
Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, 33521, Finland.
141
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
142
Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere, 33014, Finland.
143
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, 3002, Australia.
144
Centre for Ophthalmology and Vision Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, 6009, Australia.
145
Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, 7000, Australia.
146
Generation Scotland, Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
147
Musculoskeletal Research Programme, Division of Applied Medicine, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
148
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, 7600, Norway.
149
AMC, Department of Vascular Medicine, Amsterdam, 1105 AZ, The Netherlands.
150
HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, 7600, Norway.
151
Department of Neurology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands.
152
Department of Radiology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands.
153
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
154
Department of Public Health &Clinical Medicine, Umeå University, Umeå, SE-90185, Sweden.
155
Research Unit Skellefteå, Skellefteå, SE-93141, Sweden.
156
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
157
The Copenhagen City Heart Study, Frederiksberg Hospital, Frederiksberg, 2000, Denmark.
158
Department of Preventive Medicine, Keck School of Medicine of the University of California, Los Angeles, California 90089, USA.
159
USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90089, USA.
160
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, 5021, Norway.
161
National Institute of Public Health, University of Southern Denmark, Copenhagen, 1353, Denmark.
162
Steno Diabetes Center, Gentofte, 2820, Denmark.
163
Aalborg University, Aalborg, DK-9000, Denmark.
164
Research Center for Prevention and Health, Capital Region of Denmark, Glostrup, DK-2600, Denmark.
165
National Institute for Health and Welfare, Helsinki, FI-00271, Finland.
166
Department of Cardiology, Leiden University Medical Center, Leiden, 2333, The Netherlands.
167
The Interuniversity Cardiology Institute of the Netherlands, Utrecht, 2333, The Netherlands.
168
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.
169
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
170
Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA.
171
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands.
172
Department of Clinical Physiology, University of Tampere School of Medicine, Tampere, 33014, Finland.
173
Echinos Medical Centre, Echinos, Greece.
174
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK.
175
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford OX3 7LE, UK.
176
UKCRC Centre of Excellence for Public Health Research, Queens University Belfast, Belfast BT12 6BJ, UK.
177
Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, The Netherlands.
178
Department of Restorative Dentistry, Periodontology and Endodontology, University Medicine Greifswald, Greifswald, 17475, Germany.
179
Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, 70100, Finland.
180
National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
181
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
182
German Center for Diabetes Research, München-Neuherberg, 85764, Germany.
183
Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
184
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
185
Department of Psychiatry, and Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Western Cape, 7505, South Africa.
186
CHU Nantes, Service de Génétique Médicale, Nantes, 44093, France.
187
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, 70210, Finland.
188
Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', Trieste, 34137, Italy.
189
Institute of Biomedicine &Physiology, University of Eastern Finland, Kuopio, 70210, Finland.
190
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27514, USA.
191
Department of Biostatistical Sciences and Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
192
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
193
Group Health Research Institute, Seattle, Washington 98101, USA.
194
Department of Health Services, University of Washington, Seattle, Washington 98101, USA.
195
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
196
School of Medicine, National Yang-Ming University, Taipei 112, Taiwan.
197
School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
198
Division of Preventive Medicine University of Alabama at Birmingham, Birmingham, Alabama 35205, USA.
199
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People's Republic of China, Shanghai, 200031, China.
200
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California 94304, USA.
201
Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
202
Uppsala University, Uppsala, 75185, Sweden.
203
Department of Experimental Medicine, Rigshospitalet, Copenhagen, DK-2200, Denmark.
204
Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
205
Division of Health Sciences, Warwick Medical School, Warwick University, Coventry CV4 7AL, UK.
206
Department of Psychiatry, Washington University, Saint Louis, Missouri 63110, USA.
207
Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, 14558, Germany.
208
Westmead Millennium Institute of Medical Research, Centre for Vision Research and Department of Ophthalmology, University of Sydney, Sydney, New South Wales, 2022, Australia.
209
Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
210
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh EH8 9AG, UK.
211
Department of Medicine I, Ludwig-Maximilians-Universität, Munich, 81377, Germany.
212
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, 80802, Germany.
213
Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, Maryland 20892, USA.
214
DZHK (German Centre for Cardiovascular Research), partner site Greifswald, Greifswald, 17475, Germany.
215
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
216
Department of Cardiology, Heart Center, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, 33521, Finland.
217
Program in Personalized Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
218
Department of Medicine, Tampere University Hospital, Tampere, 33521, Finland.
219
Center for Neurobehavioral Genetics, UCLA, Los Angeles, California 90095, USA.
220
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
221
Laboratory of Clinical Chemistry and Hematology, Division Laboratories and Pharmacy, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
222
Laboratory of Experimental Cardiology, Division Heart &Lungs, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
223
School of Women's and Infants' Health, The University of Western Australia, Perth, Western Australia, 6009, Australia.
224
University of Helsinki, Institute for Molecular Medicine (FIMM) and Diabetes and Obesity Research Program, Helsinki, FI00014, Finland.
225
University of Tartu, Estonian Genome Center, Tartu, Estonia, Tartu, 51010, Estonia.
226
School of Medicine, University of Split, Split, 21000, Croatia.
227
Center for Neurogenomics and Cognitive Research, Department Complex Trait Genetics, VU University, Amsterdam, 1081 HV, The Netherlands.
228
Neuroscience Campus Amsterdam, Department Clinical Genetics, VU Medical Center, Amsterdam, 1081 HV, The Netherlands.
229
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
230
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20520, Finland.
231
Centre for Non-Communicable Diseases, Karachi, Pakistan.
232
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, 70210, Finland.
233
MRL, Merck &Co., Inc., Genetics and Pharmacogenomics, Boston, Massachusetts 02115, USA.
234
Department of Epidemiology, University of Washington, Seattle, Washington 98195, USA.
235
Department of Biobank Research, Umeå University, Umeå, SE-90187, Sweden.
236
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
237
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, H3T 1J4, Canada.
238
Department of Public Health and Clinical Medicine, Unit of Family Medicine, Umeå University, Umeå, 90185, Sweden.
239
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
240
Division of Epidemiology &Community Health University of Minnesota, Minneapolis, Minnesota 55454, USA.
241
Duke University, Durham, North Carolina 27703, USA.
242
Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore.
243
Departement of Haematology, University of Cambridge, Cambridge CB2 OPT, UK.
244
Department of Vascular Medicine, AMC, Amsterdam, 1105 AZ, The Netherlands.
245
Department of Twin Research and Genetic Epidemiology, Kingís College London, London SE1 7EH, UK.
246
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK.
247
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, 1007MB, The Netherlands.
248
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands.
249
Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, 2333ZC, The Netherlands.
250
College of Biomedical and Life Sciences, Cardiff University, Cardiff, CF14 4EP, UK.
251
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
252
Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17475, Germany.
253
Center for Pediatric Research, Department for Women's and Child Health, University of Leipzig, Leipzig, 04103, Germany.
254
Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Western Cape, 7505, South Africa.
255
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2333, The Netherlands.
256
Anogia Medical Centre, Anogia, Greece.
257
Centre for Vascular Prevention, Danube-University Krems, Krems, 3500, Austria.
258
Dasman Diabetes Institute, Dasman, 15462, Kuwait.
259
Diabetes Research Group, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
260
Department of Psychiatry, Dalhousie University, Halifax B3H 4R2, Canada.
261
University of Amsterdam, Department of Brain &Cognition, Amsterdam, 1018 WS, The Netherlands.
262
Department of Obstetrics and Gynecology, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee 37203, USA.
263
MRL, Merck &Co., Inc., Cardiometabolic Disease, Kenilworth, New Jersey 07033, USA.
264
Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle NE2 4HH, UK.
265
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
266
Departments of Epidemiology &Medicine, Diabetes Translational Research Center, Fairbanks School of Public Health &School of Medicine, Indiana University, Indiana 46202, USA.
267
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
268
Danish Diabetes Academy, Odense, 5000, Denmark.
269
Department of Public Health, Aarhus University, Aarhus, 8000, Denmark.
270
Memorial University, Faculty of Medicine, Discipline of Genetics, St. John's, Newfoundland A1B 3V6, Canada.
271
GlaxoSmithKlein, King of Prussia, Pennsylvania 19406, USA.
272
Department of Clinical Sciences, Quantitative Biomedical Research Center, Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
273
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
274
Department of Public Health Sciences, Institute for Personalized Medicine, the Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
275
Department of Epidemiology and Carolina Center of Genome Sciences, Chapel Hill, North Carolina 27514, USA.
276
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
277
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2200, Denmark.
278
Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford OX3 7BN, UK.
279
The Mindich Child Health and Development Institute, Ichan School of Medicine at Mount Sinai, New York, New York 10069, USA.
280
Departments of Pediatrics and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
281
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

Comment in

PMID:
28146470
PMCID:
PMC5302847
DOI:
10.1038/nature21039
[Indexed for MEDLINE]
Free PMC Article

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