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

Aurélien Macé, Marcus A. Tuke, Patrick Deelen, Kati Kristiansson, Hannele Mattsson, Margit Nõukas, Yadav Sapkota, Ursula Schick, Eleonora Porcu, Sina Rüeger, Aaron F. McDaid, David Porteous, Thomas W. Winkler, Erika Salvi, Nick Shrine, Xueping Liu, Wei Q. Ang, Weihua Zhang, Mary F. Feitosa, Cristina Venturini, Peter J. Most, Anders Rosengren, Andrew R. Wood, Robin N. Beaumont, Samuel E. Jones, Katherine S. Ruth, Hanieh Yaghootkar, Jessica Tyrrell, Aki S. Havulinna, Harmen Boers, Reedik Mägi, Jennifer Kriebel, Martina Müller-Nurasyid, Markus Perola, Markku Nieminen, Marja-Liisa Lokki, Mika Kähönen, Jorma S. Viikari, Frank Geller, Jari Lahti, Aarno Palotie, Päivikki Koponen, Annamari Lundqvist, Harri Rissanen, Erwin P. Bottinger, Saima Afaq, Mary K. Wojczynski, Petra Lenzini, Ilja M. Nolte, Thomas Sparsø, Nicole Schupf, Kaare Christensen, Thomas T. Perls, Anne B. Newman, Thomas Werge, Harold Snieder, Timothy D. Spector, John C. Chambers, Seppo Koskinen, Mads Melbye, Olli T. Raitakari, Terho Lehtimäki, Martin D. Tobin, Louise V. Wain, Juha Sinisalo, Annette Peters, Thomas Meitinger, Nicholas G. Martin, Naomi R. Wray, Grant W. Montgomery, Sarah E. Medland, Morris A. Swertz, Erkki Vartiainen, Katja Borodulin, Satu Männistö, Anna Murray, Murielle Bochud, Sébastien Jacquemont, Fernando Rivadeneira, Thomas F. Hansen, Albertine J. Oldehinkel, Massimo Mangino, Michael A. Province, Panos Deloukas, Jaspal S. Kooner, Rachel M. Freathy, Craig Pennell, Bjarke Feenstra, David P. Strachan, Guillaume Lettre, Joel Hirschhorn, Daniele Cusi, Iris M. Heid, Caroline Hayward, Katrin Männik, Jacques S. Beckmann, Ruth J. F. Loos, Dale R. Nyholt, Andres Metspalu, Johan G. Eriksson, Michael N. Weedon, Veikko Salomaa, Lude Franke, Alexandre Reymond, Timothy M. Frayling and Zoltán Kutalik ()
Additional contact information
Aurélien Macé: Lausanne University Hospital
Marcus A. Tuke: University of Exeter Medical School, University of Exeter
Patrick Deelen: University of Groningen, University Medical Center Groningen
Kati Kristiansson: National Institute for Health and Welfare
Hannele Mattsson: National Institute for Health and Welfare
Margit Nõukas: University of Tartu
Yadav Sapkota: QIMR Berghofer Medical Research Institute
Ursula Schick: Icahn School of Medicine at Mount Sinai
Eleonora Porcu: Swiss Institute of Bioinformatics
Sina Rüeger: Lausanne University Hospital
Aaron F. McDaid: Lausanne University Hospital
David Porteous: University of Edinburgh
Thomas W. Winkler: University of Regensburg
Erika Salvi: University of Milano
Nick Shrine: University of Leicester
Xueping Liu: Statens Serum Institut
Wei Q. Ang: The University of Western Australia
Weihua Zhang: Imperial College London
Mary F. Feitosa: Washington University School of Medicine
Cristina Venturini: King’s College London
Peter J. Most: University of Groningen, University Medical Center Groningen
Anders Rosengren: Mental Health Center Sct. Hans
Andrew R. Wood: University of Exeter Medical School, University of Exeter
Robin N. Beaumont: University of Exeter Medical School, University of Exeter
Samuel E. Jones: University of Exeter Medical School, University of Exeter
Katherine S. Ruth: University of Exeter Medical School, University of Exeter
Hanieh Yaghootkar: University of Exeter Medical School, University of Exeter
Jessica Tyrrell: University of Exeter Medical School, University of Exeter
Aki S. Havulinna: National Institute for Health and Welfare
Harmen Boers: University of Groningen, University Medical Center Groningen
Reedik Mägi: University of Tartu
Jennifer Kriebel: German Research Center for Environmental Health
Martina Müller-Nurasyid: Helmholtz Zentrum München—German Research Center for Environmental Health
Markus Perola: National Institute for Health and Welfare
Markku Nieminen: Heart and Lung Centre HUCH and Helsinki University
Marja-Liisa Lokki: Helsinki University
Mika Kähönen: Tampere University Hospital
Jorma S. Viikari: Turku University Hospital
Frank Geller: Statens Serum Institut
Jari Lahti: University of Helsinki
Aarno Palotie: University of Helsinki
Päivikki Koponen: National Institute for Health and Welfare
Annamari Lundqvist: National Institute for Health and Welfare
Harri Rissanen: National Institute for Health and Welfare
Erwin P. Bottinger: Icahn School of Medicine at Mount Sinai
Saima Afaq: Imperial College London
Mary K. Wojczynski: Washington University School of Medicine
Petra Lenzini: Washington University School of Medicine
Ilja M. Nolte: University of Groningen, University Medical Center Groningen
Thomas Sparsø: Mental Health Center Sct. Hans
Nicole Schupf: Columbia University
Kaare Christensen: University of Southern Denmark
Thomas T. Perls: Boston University, Boston School of Medicine and Boston Medical Center
Anne B. Newman: University of Pittsburgh Graduate School of Public Health
Thomas Werge: Mental Health Center Sct. Hans
Harold Snieder: University of Groningen, University Medical Center Groningen
Timothy D. Spector: King’s College London
John C. Chambers: Imperial College London
Seppo Koskinen: National Institute for Health and Welfare
Mads Melbye: Statens Serum Institut
Olli T. Raitakari: Turku University Hospital
Terho Lehtimäki: Fimlab Laboratories
Martin D. Tobin: University of Leicester
Louise V. Wain: University of Leicester
Juha Sinisalo: Heart and Lung Centre HUCH and Helsinki University
Annette Peters: German Research Center for Environmental Health
Thomas Meitinger: Helmholtz Zentrum München
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Naomi R. Wray: University of Queensland
Grant W. Montgomery: QIMR Berghofer Medical Research Institute
Sarah E. Medland: QIMR Berghofer Medical Research Institute
Morris A. Swertz: University of Groningen, University Medical Center Groningen
Erkki Vartiainen: National Institute for Health and Welfare
Katja Borodulin: National Institute for Health and Welfare
Satu Männistö: National Institute for Health and Welfare
Anna Murray: University of Exeter Medical School, University of Exeter
Murielle Bochud: Lausanne University Hospital
Sébastien Jacquemont: Centre Hospitalier Universitaire Sainte Justine
Fernando Rivadeneira: Erasmus Medical Center
Thomas F. Hansen: Mental Health Center Sct. Hans
Albertine J. Oldehinkel: University of Groningen, University Medical Center Groningen
Massimo Mangino: King’s College London
Michael A. Province: Washington University School of Medicine
Panos Deloukas: Queen Mary University of London
Jaspal S. Kooner: Ealing Hospital NHS Trust
Rachel M. Freathy: University of Exeter Medical School, University of Exeter
Craig Pennell: The University of Western Australia
Bjarke Feenstra: Statens Serum Institut
David P. Strachan: St. George’s, University of London
Guillaume Lettre: Université de Montréal
Joel Hirschhorn: Broad Institute of MIT and Harvard
Daniele Cusi: University of Milano
Iris M. Heid: University of Regensburg
Caroline Hayward: University of Edinburgh
Katrin Männik: University of Tartu
Jacques S. Beckmann: Swiss Institute of Bioinformatics
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Dale R. Nyholt: QIMR Berghofer Medical Research Institute
Andres Metspalu: University of Tartu
Johan G. Eriksson: University of Helsinki and Helsinki University Hospital
Michael N. Weedon: University of Exeter Medical School, University of Exeter
Veikko Salomaa: National Institute for Health and Welfare
Lude Franke: University of Groningen, University Medical Center Groningen
Alexandre Reymond: University of Lausanne
Timothy M. Frayling: University of Exeter Medical School, University of Exeter
Zoltán Kutalik: Lausanne University Hospital

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00556-x

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