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. Van Der 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; Zoltán Kutalik

doi:10.1038/s41467-017-00556-x

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. Van Der 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, Zoltán Kutalik

Medicine and Health

Centre Hospitalier Universitaire Vaudois (CHUV)
Swiss Institute of Bioinformatics
University of Lausanne
University of Exeter Medical School
University Medical Center Groningen
National Institute for Health and Welfare
University of Helsinki
University of Tartu
University of Tartu
Queensland Institute of Medical Research
St. Jude Children's Research Hospital
Mount Sinai School of Medicine
University of Edinburgh
University of Regensburg
University of Milan
University of Leicester
Statens Serum Institut
University of Western Australia
Imperial College London
Ealing Hospital NHS Trust
Washington University School of Medicine in St. Louis
King's College London
Mental Health Center Sct. Hans
Lundbeck Foundation Initiative for Integrative Psychiatric Research
Helmholtz Zentrum München German Research Center for Environmental Health
German Centre for Diabetes Research (DZD)
University of Munich
Partner Site Munich Heart Alliance
Tampere University Hospital
Tampere University
Turku University Hospital
University of Turku and Turku University Hospital
University of Helsinki
The Broad Institute of MIT and Harvard
Massachusetts General Hospital
Columbia University
University of Southern Denmark
Boston University School of Medicine
University of Pittsburgh Graduate School of Public Health
University of Copenhagen
Imperial College Healthcare NHS Trust
Stanford University School of Medicine
University of Turku
Fimlab Laboratories
Glenfield Hospital
University of Queensland
Hôpital Sainte-Justine
Centre Hospitalier Universitaire Vaudois
Erasmus University Medical Center
NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust
Barts and The London School of Medicine and Dentistry
King Abdulaziz University
National Heart and Lung Institute
St George's Hospital
H1 T 1C8
Université de Montréal
Boston Children's Hospital
Harvard Medical School
Institute of Biomedical Technologies-CNR
MRC Human Genetics Unit
Queensland University of Technology
Helsinki University Central Hospital
Folkhälsan

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

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.

Original language	English
Article number	744
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00556-x
State	Published - 1 Dec 2017

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Macé, A., Tuke, M. A., Deelen, P., Kristiansson, K., Mattsson, H., Nõukas, M., Sapkota, Y., Schick, U., Porcu, E., Rüeger, S., McDaid, A. F., Porteous, D., Winkler, T. W., Salvi, E., Shrine, N., Liu, X., Ang, W. Q., Zhang, W., Feitosa, M. F., ... Kutalik, Z. (2017). CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits. Nature Communications, 8(1), Article 744. https://doi.org/10.1038/s41467-017-00556-x

@article{11fb28a9bd0241278e497e898aca8ec2,

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

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.",

author = "Aur{\'e}lien Mac{\'e} and Tuke, \{Marcus A.\} and Patrick Deelen and Kati Kristiansson and Hannele Mattsson and Margit N{\~o}ukas and Yadav Sapkota and Ursula Schick and Eleonora Porcu and Sina R{\"u}eger and McDaid, \{Aaron F.\} and David Porteous and Winkler, \{Thomas W.\} and Erika Salvi and Nick Shrine and Xueping Liu and Ang, \{Wei Q.\} and Weihua Zhang and Feitosa, \{Mary F.\} and Cristina Venturini and \{Van Der Most\}, \{Peter J.\} and Anders Rosengren and Wood, \{Andrew R.\} and Beaumont, \{Robin N.\} and Jones, \{Samuel E.\} and Ruth, \{Katherine S.\} and Hanieh Yaghootkar and Jessica Tyrrell and Havulinna, \{Aki S.\} and Harmen Boers and Reedik M{\"a}gi and Jennifer Kriebel and Martina M{\"u}ller-Nurasyid and Markus Perola and Markku Nieminen and Lokki, \{Marja Liisa\} and Mika K{\"a}h{\"o}nen and Viikari, \{Jorma S.\} and Frank Geller and Jari Lahti and Aarno Palotie and P{\"a}ivikki Koponen and Annamari Lundqvist and Harri Rissanen and Bottinger, \{Erwin P.\} and Saima Afaq and Wojczynski, \{Mary K.\} and Petra Lenzini and Nolte, \{Ilja M.\} and Thomas Spars{\o} and Nicole Schupf and Kaare Christensen and Perls, \{Thomas T.\} and Newman, \{Anne B.\} and Thomas Werge and Harold Snieder and Spector, \{Timothy D.\} and Chambers, \{John C.\} and Seppo Koskinen and Mads Melbye and Raitakari, \{Olli T.\} and Terho Lehtim{\"a}ki and Tobin, \{Martin D.\} and Wain, \{Louise V.\} and Juha Sinisalo and Annette Peters and Thomas Meitinger and Martin, \{Nicholas G.\} and Wray, \{Naomi R.\} and Montgomery, \{Grant W.\} and Medland, \{Sarah E.\} and Swertz, \{Morris A.\} and Erkki Vartiainen and Katja Borodulin and Satu M{\"a}nnist{\"o} and Anna Murray and Murielle Bochud and S{\'e}bastien Jacquemont and Fernando Rivadeneira and Hansen, \{Thomas F.\} and Oldehinkel, \{Albertine J.\} and Massimo Mangino and Province, \{Michael A.\} and Panos Deloukas and Kooner, \{Jaspal S.\} and Freathy, \{Rachel M.\} and Craig Pennell and Bjarke Feenstra and Strachan, \{David P.\} and Guillaume Lettre and Joel Hirschhorn and Daniele Cusi and Heid, \{Iris M.\} and Caroline Hayward and Katrin M{\"a}nnik and Beckmann, \{Jacques S.\} and Loos, \{Ruth J.F.\} and Nyholt, \{Dale R.\} and Andres Metspalu and Eriksson, \{Johan G.\} and Weedon, \{Michael N.\} and Veikko Salomaa and Lude Franke and Alexandre Reymond and Frayling, \{Timothy M.\} and Zolt{\'a}n Kutalik",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00556-x",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Macé, A, Tuke, MA, Deelen, P, Kristiansson, K, Mattsson, H, Nõukas, M, Sapkota, Y, Schick, U, Porcu, E, Rüeger, S, McDaid, AF, Porteous, D, Winkler, TW, Salvi, E, Shrine, N, Liu, X, Ang, WQ, Zhang, W, Feitosa, MF, Venturini, C, Van Der Most, PJ, Rosengren, A, Wood, AR, Beaumont, RN, Jones, SE, Ruth, KS, Yaghootkar, H, Tyrrell, J, Havulinna, AS, Boers, H, Mägi, R, Kriebel, J, Müller-Nurasyid, M, Perola, M, Nieminen, M, Lokki, ML, Kähönen, M, Viikari, JS, Geller, F, Lahti, J, Palotie, A, Koponen, P, Lundqvist, A, Rissanen, H, Bottinger, EP, Afaq, S, Wojczynski, MK, Lenzini, P, Nolte, IM, Sparsø, T, Schupf, N, Christensen, K, Perls, TT, Newman, AB, Werge, T, Snieder, H, Spector, TD, Chambers, JC, Koskinen, S, Melbye, M, Raitakari, OT, Lehtimäki, T, Tobin, MD, Wain, LV, Sinisalo, J, Peters, A, Meitinger, T, Martin, NG, Wray, NR, Montgomery, GW, Medland, SE, Swertz, MA, Vartiainen, E, Borodulin, K, Männistö, S, Murray, A, Bochud, M, Jacquemont, S, Rivadeneira, F, Hansen, TF, Oldehinkel, AJ, Mangino, M, Province, MA, Deloukas, P, Kooner, JS, Freathy, RM, Pennell, C, Feenstra, B, Strachan, DP, Lettre, G, Hirschhorn, J, Cusi, D, Heid, IM, Hayward, C, Männik, K, Beckmann, JS, Loos, RJF, Nyholt, DR, Metspalu, A, Eriksson, JG, Weedon, MN, Salomaa, V, Franke, L, Reymond, A, Frayling, TM & Kutalik, Z 2017, 'CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits', Nature Communications, vol. 8, no. 1, 744. https://doi.org/10.1038/s41467-017-00556-x

TY - JOUR

T1 - CNV-association meta-analysis in 191,161 European adults reveals new loci associated with anthropometric traits

AU - Macé, Aurélien

AU - Tuke, Marcus A.

AU - Deelen, Patrick

AU - Kristiansson, Kati

AU - Mattsson, Hannele

AU - Nõukas, Margit

AU - Sapkota, Yadav

AU - Schick, Ursula

AU - Porcu, Eleonora

AU - Rüeger, Sina

AU - McDaid, Aaron F.

AU - Porteous, David

AU - Winkler, Thomas W.

AU - Salvi, Erika

AU - Shrine, Nick

AU - Liu, Xueping

AU - Ang, Wei Q.

AU - Zhang, Weihua

AU - Feitosa, Mary F.

AU - Venturini, Cristina

AU - Van Der Most, Peter J.

AU - Rosengren, Anders

AU - Wood, Andrew R.

AU - Beaumont, Robin N.

AU - Jones, Samuel E.

AU - Ruth, Katherine S.

AU - Yaghootkar, Hanieh

AU - Tyrrell, Jessica

AU - Havulinna, Aki S.

AU - Boers, Harmen

AU - Mägi, Reedik

AU - Kriebel, Jennifer

AU - Müller-Nurasyid, Martina

AU - Perola, Markus

AU - Nieminen, Markku

AU - Lokki, Marja Liisa

AU - Kähönen, Mika

AU - Viikari, Jorma S.

AU - Geller, Frank

AU - Lahti, Jari

AU - Palotie, Aarno

AU - Koponen, Päivikki

AU - Lundqvist, Annamari

AU - Rissanen, Harri

AU - Bottinger, Erwin P.

AU - Afaq, Saima

AU - Wojczynski, Mary K.

AU - Lenzini, Petra

AU - Nolte, Ilja M.

AU - Sparsø, Thomas

AU - Schupf, Nicole

AU - Christensen, Kaare

AU - Perls, Thomas T.

AU - Newman, Anne B.

AU - Werge, Thomas

AU - Snieder, Harold

AU - Spector, Timothy D.

AU - Chambers, John C.

AU - Koskinen, Seppo

AU - Melbye, Mads

AU - Raitakari, Olli T.

AU - Lehtimäki, Terho

AU - Tobin, Martin D.

AU - Wain, Louise V.

AU - Sinisalo, Juha

AU - Peters, Annette

AU - Meitinger, Thomas

AU - Martin, Nicholas G.

AU - Wray, Naomi R.

AU - Montgomery, Grant W.

AU - Medland, Sarah E.

AU - Swertz, Morris A.

AU - Vartiainen, Erkki

AU - Borodulin, Katja

AU - Männistö, Satu

AU - Murray, Anna

AU - Bochud, Murielle

AU - Jacquemont, Sébastien

AU - Rivadeneira, Fernando

AU - Hansen, Thomas F.

AU - Oldehinkel, Albertine J.

AU - Mangino, Massimo

AU - Province, Michael A.

AU - Deloukas, Panos

AU - Kooner, Jaspal S.

AU - Freathy, Rachel M.

AU - Pennell, Craig

AU - Feenstra, Bjarke

AU - Strachan, David P.

AU - Lettre, Guillaume

AU - Hirschhorn, Joel

AU - Cusi, Daniele

AU - Heid, Iris M.

AU - Hayward, Caroline

AU - Männik, Katrin

AU - Beckmann, Jacques S.

AU - Loos, Ruth J.F.

AU - Nyholt, Dale R.

AU - Metspalu, Andres

AU - Eriksson, Johan G.

AU - Weedon, Michael N.

AU - Salomaa, Veikko

AU - Franke, Lude

AU - Reymond, Alexandre

AU - Frayling, Timothy M.

AU - Kutalik, Zoltán

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85030331328

U2 - 10.1038/s41467-017-00556-x

DO - 10.1038/s41467-017-00556-x

M3 - Article

C2 - 28963451

AN - SCOPUS:85030331328

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 744

ER -

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

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