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 VenturiniPeter 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

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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 - Dec 1 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), [744]. https://doi.org/10.1038/s41467-017-00556-x

@article{0fd554b39601401488b05f71916e6670,

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 = "Funding Information: This research has been conducted using the UK Biobank Resource. This research has been conducted using the Danish National Biobank resource. The authors are grateful to the Raine Study participants and their families, and to the Raine Study research staff for cohort co-ordination and data collection. QIMR is grateful to the twins and their families for their generous participation in these studies. We would like to thank staff at the Queensland Institute of Medical Research: Anjali Henders, Dixie Statham, Lisa Bowdler, Ann Eldridge, and Marlene Grace for sample collection, processing and genotyping, Scott Gordon, Brian McEvoy, Belinda Cornes and Beben Benyamin for data QC and preparation, and David Smyth and Harry Beeby for IT support. HBCS Acknowledgements: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkh{\"a}lsan Research Foundation, Novo Nordisk Foundation, Finska L{\"a}kares{\"a}llskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. Finrisk study is grateful for the THL DNA laboratory for its skillful work to produce the DNA samples used in this study and thanks the Sanger Institute and FIMM genotyping facilities for genotyping the samples. We thank the MOLGENIS team and Genomics Coordination Center of the University Medical Center Groningen for software development and data management, in particular Marieke Bijlsma and Edith Adriaanse. This work was supported by the Leenards Foundation (to Z.K.), the Swiss National Science Foundation (31003A_169929 to Z.K., Sinergia grant CRSII33-133044 to AR), Simons Foundation (SFARI274424 to AR) and SystemsX.ch (51RTP0_151019 to Z.K.). A.R.W., H.Y. and T.M.F. are supported by the European Research Council grant: 323195:SZ-245. M.A.T., M.N.W. and An.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). For full funding information of all participating cohorts see Supplementary Note 2. 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",

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

N1 - Funding Information: This research has been conducted using the UK Biobank Resource. This research has been conducted using the Danish National Biobank resource. The authors are grateful to the Raine Study participants and their families, and to the Raine Study research staff for cohort co-ordination and data collection. QIMR is grateful to the twins and their families for their generous participation in these studies. We would like to thank staff at the Queensland Institute of Medical Research: Anjali Henders, Dixie Statham, Lisa Bowdler, Ann Eldridge, and Marlene Grace for sample collection, processing and genotyping, Scott Gordon, Brian McEvoy, Belinda Cornes and Beben Benyamin for data QC and preparation, and David Smyth and Harry Beeby for IT support. HBCS Acknowledgements: We thank all study participants as well as everybody involved in the Helsinki Birth Cohort Study. Helsinki Birth Cohort Study has been supported by grants from the Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Juho Vainio Foundation, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, Emil Aaltonen Foundation. Finrisk study is grateful for the THL DNA laboratory for its skillful work to produce the DNA samples used in this study and thanks the Sanger Institute and FIMM genotyping facilities for genotyping the samples. We thank the MOLGENIS team and Genomics Coordination Center of the University Medical Center Groningen for software development and data management, in particular Marieke Bijlsma and Edith Adriaanse. This work was supported by the Leenards Foundation (to Z.K.), the Swiss National Science Foundation (31003A_169929 to Z.K., Sinergia grant CRSII33-133044 to AR), Simons Foundation (SFARI274424 to AR) and SystemsX.ch (51RTP0_151019 to Z.K.). A.R.W., H.Y. and T.M.F. are supported by the European Research Council grant: 323195:SZ-245. M.A.T., M.N.W. and An.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). For full funding information of all participating cohorts see Supplementary Note 2. Publisher Copyright: © 2017 The Author(s).

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 - http://www.scopus.com/inward/record.url?scp=85030331328&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-00556-x

DO - 10.1038/s41467-017-00556-x

M3 - Article

C2 - 28963451

AN - SCOPUS:85030331328

VL - 8

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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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