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Nat Commun. 2017 Sep 29;8(1):744. doi: 10.1038/s41467-017-00556-x.

CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits.

Macé A1,2,3, Tuke MA4, Deelen P5,6, Kristiansson K7,8, Mattsson H7,8, Nõukas M9,10, Sapkota Y11,12, Schick U13, Porcu E2,14, Rüeger S1,2, McDaid AF1,2, Porteous D15, Winkler TW16, Salvi E17, Shrine N18, Liu X19, Ang WQ20, Zhang W21,22, Feitosa MF23, Venturini C24, van der Most PJ25, Rosengren A26,27, Wood AR4, Beaumont RN4, Jones SE4, Ruth KS4, Yaghootkar H4, Tyrrell J4, Havulinna AS7, Boers H5,6, Mägi R9, Kriebel J28,29,30, Müller-Nurasyid M31,32,33, Perola M7,34, Nieminen M35, Lokki ML36, Kähönen M37,38, Viikari JS39,40, Geller F19, Lahti J41,42, Palotie A8,43,44, Koponen P7, Lundqvist A7, Rissanen H7, Bottinger EP13, Afaq S21, Wojczynski MK23, Lenzini P23, Nolte IM25, Sparsø T26,27, Schupf N45, Christensen K46, Perls TT47, Newman AB48, Werge T26,27,49, Snieder H25, Spector TD24, Chambers JC21,22,50, Koskinen S7, Melbye M19,51,52, Raitakari OT53,54, Lehtimäki T55,56, Tobin MD18,57, Wain LV18,57, Sinisalo J35, Peters A29,30,33, Meitinger T58,59, Martin NG60, Wray NR61, Montgomery GW11,62, Medland SE11, Swertz MA5,6, Vartiainen E7, Borodulin K7, Männistö S7, Murray A4, Bochud M1, Jacquemont S63,64, Rivadeneira F65,66, Hansen TF26,27, Oldehinkel AJ67, Mangino M24,68, Province MA23, Deloukas P69,70, Kooner JS22,50,71, Freathy RM4, Pennell C20, Feenstra B19, Strachan DP72, Lettre G73,74, Hirschhorn J75,76,77, Cusi D17,78, Heid IM16, Hayward C79, Männik K9,14, Beckmann JS2, Loos RJF13,80, Nyholt DR11,81, Metspalu A9, Eriksson JG82,83, Weedon MN4, Salomaa V7, Franke L5, Reymond A14, Frayling TM4, Kutalik Z84,85.

Author information

1
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland.
2
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland.
3
Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland.
4
Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, EX2 5DW, UK.
5
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
6
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, 9713 GZ, The Netherlands.
7
National Institute for Health and Welfare, Helsinki, 00271, Finland.
8
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, FI-00014, Finland.
9
Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.
10
Institute of Molecular and Cell Biology, University of Tartu, Tartu, 51010, Estonia.
11
QIMR Berghofer Medical Research Institute, Brisbane, 4006, Australia.
12
St. Jude Children's Research hospital, Memphis, TN, 38105, USA.
13
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
14
Center for Integrative Genomics, University of Lausanne, Lausanne, 1015, Switzerland.
15
Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
16
Department of Genetic Epidemiology, University of Regensburg, Regensburg, 93053, Germany.
17
Department of Health Sciences, University of Milano, Milano, 20090, Italy.
18
Department of Health Sciences, University of Leicester, Leicester, LE1 7RH, UK.
19
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, 2300, Denmark.
20
School of Women's and Infants' Health, The University of Western Australia, Perth, 6009, Australia.
21
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
22
Department of Cardiology, Ealing Hospital NHS Trust, Uxbridge Road, Southall, Middlesex, UB1 3EU, UK.
23
Department of Genetics, Washington University School of Medicine, St. Louis, 63108, USA.
24
Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.
25
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
26
Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Roskilde, 4000, Denmark.
27
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, 8210, Denmark.
28
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
29
Institute of Epidemiology II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
30
German Center for Diabetes Research (DZD), Muenchen-Neuherberg, 85764, Germany.
31
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
32
Department of Medicine I, Ludwig-Maximilians-Universität, Munich, 81337, Germany.
33
DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, 80336, Germany.
34
University of Tartu, Estonian Genome Center, Tartu, 51010, Estonia.
35
Heart and Lung Centre HUCH and Helsinki University, Helsinki, 00029, Finland.
36
Medicum, Helsinki University, Helsinki, 00014, Finland.
37
Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland.
38
Department of Clinical Physiology, University of Tampere Faculty of Medicine and Life Sciences, Tampere, 33521, Finland.
39
Division of Medicine, Turku University Hospital, Turku, 20521, Finland.
40
Department of Medicine, University of Turku, Turku, 20521, Finland.
41
Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.
42
Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, 00014, Finland.
43
The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
44
Analytic and Translational Genetics Unit, Department of Medicine and Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA.
45
Taub Institute, College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
46
The Danish Aging Research Center, Epidemiology, University of Southern Denmark, Odense, 5000, Denmark.
47
Section of Geriatrics, Department of Medicine, Boston University, Boston School of Medicine and Boston Medical Center, Boston, MA, 02118, USA.
48
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, 15261, USA.
49
Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen, Copenhagen, 2200, Denmark.
50
Imperial College Healthcare NHS Trust, London, W12 0HS, UK.
51
Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark.
52
Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
53
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
54
Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20521, Finland.
55
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33521, Finland.
56
Department of Clinical Chemistry, University of Tampere Faculty of Medicine and Life Sciences, Tampere, 33521, Finland.
57
National Institute for Health Research, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, LE3 9QP, UK.
58
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, 85764, Germany.
59
Institute of Human Genetics, Technische Universität München, Munich, 81675, Germany.
60
QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
61
Queensland Brain Institute, University of Queensland, Brisbane, QLD, 4072, Australia.
62
The Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia.
63
Centre de recherche, Centre Hospitalier Universitaire Sainte Justine, Montréal, Canada, H3T 1C5.
64
Service of Medical Genetics, University Hospital of Lausanne, University of Lausanne, Lausanne, 1011, Switzerland.
65
Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands.
66
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015 GE, The Netherlands.
67
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, 9713 GZ, The Netherlands.
68
NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, SE1 9RT, UK.
69
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
70
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
71
National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
72
Population Health Research Institute, St. George's, University of London, London, SW17 0RE, UK.
73
Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada, H1T 1C8.
74
Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada, H3T 1J4.
75
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
76
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
77
Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
78
Institute of Biomedical Technologies, Italian National Research Council, Milano, 20090, Italy.
79
Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
80
The Genetics of Obesity and Related Metabolic Traits Program, Icahn School of Medicine at Mount Sinai, New York, 10029, USA.
81
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 4059, Australia.
82
Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland.
83
Folkhälsan Research Center, Helsinki, 00250, Finland.
84
Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland. zoltan.kutalik@unil.ch.
85
Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland. zoltan.kutalik@unil.ch.

Abstract

There are few examples of robust associations between rare copy number variants (CNVs) and complex continuous human traits. Here we present a large-scale CNV association meta-analysis on anthropometric traits in up to 191,161 adult samples from 26 cohorts. The study reveals five CNV associations at 1q21.1, 3q29, 7q11.23, 11p14.2, and 18q21.32 and confirms two known loci at 16p11.2 and 22q11.21, implicating at least one anthropometric trait. The discovered CNVs are recurrent and rare (0.01-0.2%), with large effects on height (>2.4 cm), weight (>5 kg), and body mass index (BMI) (>3.5 kg/m2). Burden analysis shows a 0.41 cm decrease in height, a 0.003 increase in waist-to-hip ratio and increase in BMI by 0.14 kg/m2 for each Mb of total deletion burden (P = 2.5 × 10-10, 6.0 × 10-5, and 2.9 × 10-3). Our study provides evidence that the same genes (e.g., MC4R, FIBIN, and FMO5) harbor both common and rare variants affecting body size and that anthropometric traits share genetic loci with developmental and psychiatric disorders.Individual SNPs have small effects on anthropometric traits, yet the impact of CNVs has remained largely unknown. Here, Kutalik and co-workers perform a large-scale genome-wide meta-analysis of structural variation and find rare CNVs associated with height, weight and BMI with large effect sizes.

PMID:
28963451
PMCID:
PMC5622064
DOI:
10.1038/s41467-017-00556-x
[Indexed for MEDLINE]
Free PMC Article

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