Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Christian R. Marshall; Daniel P. Howrigan; Daniele Merico; Bhooma Thiruvahindrapuram; Wenting Wu; Douglas S. Greer; Danny Antaki; Aniket Shetty; Peter A. Holmans; Dalila Pinto; Madhusudan Gujral; William M. Brandler; Dheeraj Malhotra; Zhouzhi Wang; Karin V. Fuentes Fajarado; Michelle S. Maile; Stephan Ripke; Ingrid Agartz; Margot Albus; Madeline Alexander; Farooq Amin; Joshua Atkins; Silviu A. Bacanu; Richard A. Belliveau; Sarah E. Bergen; Marcelo Bertalan; Elizabeth Bevilacqua; Tim B. Bigdeli; Donald W. Black; Richard Bruggeman; Nancy G. Buccola; Randy L. Buckner; Brendan Bulik-Sullivan; William Byerley; Wiepke Cahn; Guiqing Cai; Murray J. Cairns; Dominique Campion; Rita M. Cantor; Vaughan J. Carr; Noa Carrera; Stanley V. Catts; Kimberley D. Chambert; Wei Cheng; C. Robert Cloninger; David Cohen; Paul Cormican; Nick Craddock; Benedicto Crespo-Facorro; James J. Crowley; David Curtis; Michael Davidson; Kenneth L. Davis; Franziska Degenhardt; Jurgen Del Favero; Lynn E. DeLisi; Dimitris Dikeos; Timothy Dinan; Srdjan Djurovic; Gary Donohoe; Elodie Drapeau; Jubao Duan; Frank Dudbridge; Peter Eichhammer; Johan Eriksson; Valentina Escott-Price; Laurent Essioux; Ayman H. Fanous; Kai How Farh; Martilias S. Farrell; Josef Frank; Lude Franke; Robert Freedman; Nelson B. Freimer; Joseph I. Friedman; Andreas J. Forstner; Menachem Fromer; Giulio Genovese; Lyudmila Georgieva; Elliot S. Gershon; Ina Giegling; Paola Giusti-Rodríguez; Stephanie Godard; Jacqueline I. Goldstein; Jacob Gratten; Lieuwe De Haan; Marian L. Hamshere; Mark Hansen; Thomas Hansen; Vahram Haroutunian; Annette M. Hartmann; Frans A. Henskens; Stefan Herms; Joel N. Hirschhorn; Per Hoffmann; Andrea Hofman; Hailiang Huang; Masashi Ikeda; Inge Joa; Anna K. Kähler; René S. Kahn; Luba Kalaydjieva; Juha Karjalainen; David Kavanagh; Matthew C. Keller; Brian J. Kelly; James L. Kennedy; Yunjung Kim; James A. Knowles; Bettina Konte; Claudine Laurent; Phil Lee; S. Hong Lee; Sophie E. Legge; Bernard Lerer; Deborah L. Levy; Kung Yee Liang; Jeffrey Lieberman; Jouko Lönnqvist; Carmel M. Loughland; Patrik K E Magnusson; Brion S. Maher; Wolfgang Maier; Jacques Mallet; Manuel Mattheisen; Morten Mattingsdal; Robert W. McCarley; Colm McDonald; Andrew M. McIntosh; Sandra Meier; Carin J. Meijer; Ingrid Melle; Raquelle I. Mesholam-Gately; Andres Metspalu; Patricia T. Michie; Lili Milani; Vihra Milanova; Younes Mokrab; Derek W. Morris; Bertram Müller-Myhsok; Kieran C. Murphy; Robin M. Murray; Inez Myin-Germeys; Igor Nenadic; Deborah A. Nertney; Gerald Nestadt; Kristin K. Nicodemus; Laura Nisenbaum; Annelie Nordin; Eadbhard O'Callaghan; Colm O'Dushlaine; Sang Yun Oh; Ann Olincy; Line Olsen; F. Anthony O'Neill; Jim Van Os; Christos Pantelis; George N. Papadimitriou; Elena Parkhomenko; Michele T. Pato; Tiina Paunio; Diana O. Perkins; Tune H. Pers; Olli Pietiläinen; Jonathan Pimm; Andrew J. Pocklington; John Powell; Alkes Price; Ann E. Pulver; Shaun M. Purcell; Digby Quested; Henrik B. Rasmussen; Abraham Reichenberg; Mark A. Reimers; Alexander L. Richards; Joshua L. Roffman; Panos Roussos; Douglas M. Ruderfer; Veikko Salomaa; Alan R. Sanders; Adam Savitz; Ulrich Schall; Thomas G. Schulze; Sibylle G. Schwab; Edward M. Scolnick; Rodney J. Scott; Larry J. Seidman; Jianxin Shi; Jeremy M. Silverman; Jordan W. Smoller; Erik Söderman; Chris C A Spencer; Eli A. Stahl; Eric Strengman; Jana Strohmaier; T. Scott Stroup; Jaana Suvisaari; Dragan M. Svrakic; Jin P. Szatkiewicz; Srinivas Thirumalai; Paul A. Tooney; Juha Veijola; Peter M. Visscher; John Waddington; Dermot Walsh; Bradley T. Webb; Mark Weiser; Dieter B. Wildenauer; Nigel M. Williams; Stephanie Williams; Stephanie H. Witt; Aaron R. Wolen; Brandon K. Wormley; Naomi R. Wray; Jing Qin Wu; Clement C. Zai; Rolf Adolfsson; Ole A. Andreassen; Douglas H R Blackwood; Elvira Bramon; Joseph D. Buxbaum; Sven Cichon; David A. Collier; Aiden Corvin; Mark J. Daly; Ariel Darvasi; Enrico Domenici; Tõnu Esko; Pablo V. Gejman; Michael Gill; Hugh Gurling; Christina M. Hultman; Nakao Iwata; Assen V. Jablensky; Erik G. Jönsson; Kenneth S. Kendler; George Kirov; Jo Knight; Douglas F. Levinson; Qingqin S. Li; Steven A. McCarroll; Andrew McQuillin; Jennifer L. Moran; Bryan J. Mowry; Markus M. Nöthen; Roel A. Ophoff; Michael J. Owen; Aarno Palotie; Carlos N. Pato; Tracey L. Petryshen; Psychosis Endophenotypes International Consortium; CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium

doi:10.1038/ng.3725

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Christian R. Marshall, Daniel P. Howrigan, Daniele Merico, Bhooma Thiruvahindrapuram, Wenting Wu, Douglas S. Greer, Danny Antaki, Aniket Shetty, Peter A. Holmans, Dalila Pinto, Madhusudan Gujral, William M. Brandler, Dheeraj Malhotra, Zhouzhi Wang, Karin V. Fuentes Fajarado, Michelle S. Maile, Stephan Ripke, Ingrid Agartz, Margot Albus, Madeline AlexanderFarooq Amin, Joshua Atkins, Silviu A. Bacanu, Richard A. Belliveau, Sarah E. Bergen, Marcelo Bertalan, Elizabeth Bevilacqua, Tim B. Bigdeli, Donald W. Black, Richard Bruggeman, Nancy G. Buccola, Randy L. Buckner, Brendan Bulik-Sullivan, William Byerley, Wiepke Cahn, Guiqing Cai, Murray J. Cairns, Dominique Campion, Rita M. Cantor, Vaughan J. Carr, Noa Carrera, Stanley V. Catts, Kimberley D. Chambert, Wei Cheng, C. Robert Cloninger, David Cohen, Paul Cormican, Nick Craddock, Benedicto Crespo-Facorro, James J. Crowley, David Curtis, Michael Davidson, Kenneth L. Davis, Franziska Degenhardt, Jurgen Del Favero, Lynn E. DeLisi, Dimitris Dikeos, Timothy Dinan, Srdjan Djurovic, Gary Donohoe, Elodie Drapeau, Jubao Duan, Frank Dudbridge, Peter Eichhammer, Johan Eriksson, Valentina Escott-Price, Laurent Essioux, Ayman H. Fanous, Kai How Farh, Martilias S. Farrell, Josef Frank, Lude Franke, Robert Freedman, Nelson B. Freimer, Joseph I. Friedman, Andreas J. Forstner, Menachem Fromer, Giulio Genovese, Lyudmila Georgieva, Elliot S. Gershon, Ina Giegling, Paola Giusti-Rodríguez, Stephanie Godard, Jacqueline I. Goldstein, Jacob Gratten, Lieuwe De Haan, Marian L. Hamshere, Mark Hansen, Thomas Hansen, Vahram Haroutunian, Annette M. Hartmann, Frans A. Henskens, Stefan Herms, Joel N. Hirschhorn, Per Hoffmann, Andrea Hofman, Hailiang Huang, Masashi Ikeda, Inge Joa, Anna K. Kähler, René S. Kahn, Luba Kalaydjieva, Juha Karjalainen, David Kavanagh, Matthew C. Keller, Brian J. Kelly, James L. Kennedy, Yunjung Kim, James A. Knowles, Bettina Konte, Claudine Laurent, Phil Lee, S. Hong Lee, Sophie E. Legge, Bernard Lerer, Deborah L. Levy, Kung Yee Liang, Jeffrey Lieberman, Jouko Lönnqvist, Carmel M. Loughland, Patrik K E Magnusson, Brion S. Maher, Wolfgang Maier, Jacques Mallet, Manuel Mattheisen, Morten Mattingsdal, Robert W. McCarley, Colm McDonald, Andrew M. McIntosh, Sandra Meier, Carin J. Meijer, Ingrid Melle, Raquelle I. Mesholam-Gately, Andres Metspalu, Patricia T. Michie, Lili Milani, Vihra Milanova, Younes Mokrab, Derek W. Morris, Bertram Müller-Myhsok, Kieran C. Murphy, Robin M. Murray, Inez Myin-Germeys, Igor Nenadic, Deborah A. Nertney, Gerald Nestadt, Kristin K. Nicodemus, Laura Nisenbaum, Annelie Nordin, Eadbhard O'Callaghan, Colm O'Dushlaine, Sang Yun Oh, Ann Olincy, Line Olsen, F. Anthony O'Neill, Jim Van Os, Christos Pantelis, George N. Papadimitriou, Elena Parkhomenko, Michele T. Pato, Tiina Paunio, Diana O. Perkins, Tune H. Pers, Olli Pietiläinen, Jonathan Pimm, Andrew J. Pocklington, John Powell, Alkes Price, Ann E. Pulver, Shaun M. Purcell, Digby Quested, Henrik B. Rasmussen, Abraham Reichenberg, Mark A. Reimers, Alexander L. Richards, Joshua L. Roffman, Panos Roussos, Douglas M. Ruderfer, Veikko Salomaa, Alan R. Sanders, Adam Savitz, Ulrich Schall, Thomas G. Schulze, Sibylle G. Schwab, Edward M. Scolnick, Rodney J. Scott, Larry J. Seidman, Jianxin Shi, Jeremy M. Silverman, Jordan W. Smoller, Erik Söderman, Chris C A Spencer, Eli A. Stahl, Eric Strengman, Jana Strohmaier, T. Scott Stroup, Jaana Suvisaari, Dragan M. Svrakic, Jin P. Szatkiewicz, Srinivas Thirumalai, Paul A. Tooney, Juha Veijola, Peter M. Visscher, John Waddington, Dermot Walsh, Bradley T. Webb, Mark Weiser, Dieter B. Wildenauer, Nigel M. Williams, Stephanie Williams, Stephanie H. Witt, Aaron R. Wolen, Brandon K. Wormley, Naomi R. Wray, Jing Qin Wu, Clement C. Zai, Rolf Adolfsson, Ole A. Andreassen, Douglas H R Blackwood, Elvira Bramon, Joseph D. Buxbaum, Sven Cichon, David A. Collier, Aiden Corvin, Mark J. Daly, Ariel Darvasi, Enrico Domenici, Tõnu Esko, Pablo V. Gejman, Michael Gill, Hugh Gurling, Christina M. Hultman, Nakao Iwata, Assen V. Jablensky, Erik G. Jönsson, Kenneth S. Kendler, George Kirov, Jo Knight, Douglas F. Levinson, Qingqin S. Li, Steven A. McCarroll, Andrew McQuillin, Jennifer L. Moran, Bryan J. Mowry, Markus M. Nöthen, Roel A. Ophoff, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Tracey L. Petryshen, Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium

UWA Centre for Medical Research (affiliated with the Harry Perkins Institute of Medical Research)

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

693 Citations (Scopus)

Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10^-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10^-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10^-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10^-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Original language	English
Pages (from-to)	27-35
Number of pages	9
Journal	Nature Genetics
Volume	49
Issue number	1
DOIs	https://doi.org/10.1038/ng.3725
Publication status	Published - 1 Jan 2017

Access to Document

10.1038/ng.3725

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737772/

Cite this

Marshall, C. R., Howrigan, D. P., Merico, D., Thiruvahindrapuram, B., Wu, W., Greer, D. S., Antaki, D., Shetty, A., Holmans, P. A., Pinto, D., Gujral, M., Brandler, W. M., Malhotra, D., Wang, Z., Fuentes Fajarado, K. V., Maile, M. S., Ripke, S., Agartz, I., Albus, M., ... CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium (2017). Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics, 49(1), 27-35. https://doi.org/10.1038/ng.3725

@article{6e288c34954743d5818661d698502793,

title = "Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects",

abstract = "Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.",

author = "Marshall, {Christian R.} and Howrigan, {Daniel P.} and Daniele Merico and Bhooma Thiruvahindrapuram and Wenting Wu and Greer, {Douglas S.} and Danny Antaki and Aniket Shetty and Holmans, {Peter A.} and Dalila Pinto and Madhusudan Gujral and Brandler, {William M.} and Dheeraj Malhotra and Zhouzhi Wang and {Fuentes Fajarado}, {Karin V.} and Maile, {Michelle S.} and Stephan Ripke and Ingrid Agartz and Margot Albus and Madeline Alexander and Farooq Amin and Joshua Atkins and Bacanu, {Silviu A.} and Belliveau, {Richard A.} and Bergen, {Sarah E.} and Marcelo Bertalan and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and Brendan Bulik-Sullivan and William Byerley and Wiepke Cahn and Guiqing Cai and Cairns, {Murray J.} and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Catts, {Stanley V.} and Chambert, {Kimberley D.} and Wei Cheng and Cloninger, {C. Robert} and David Cohen and Paul Cormican and Nick Craddock and Benedicto Crespo-Facorro and Crowley, {James J.} and David Curtis and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and {Del Favero}, Jurgen and DeLisi, {Lynn E.} and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Laurent Essioux and Fanous, {Ayman H.} and Farh, {Kai How} and Farrell, {Martilias S.} and Josef Frank and Lude Franke and Robert Freedman and Freimer, {Nelson B.} and Friedman, {Joseph I.} and Forstner, {Andreas J.} and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Gershon, {Elliot S.} and Ina Giegling and Paola Giusti-Rodr{\'i}guez and Stephanie Godard and Goldstein, {Jacqueline I.} and Jacob Gratten and {De Haan}, Lieuwe and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian and Hartmann, {Annette M.} and Henskens, {Frans A.} and Stefan Herms and Hirschhorn, {Joel N.} and Per Hoffmann and Andrea Hofman and Hailiang Huang and Masashi Ikeda and Inge Joa and K{\"a}hler, {Anna K.} and Kahn, {Ren{\'e} S.} and Luba Kalaydjieva and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kelly, {Brian J.} and Kennedy, {James L.} and Yunjung Kim and Knowles, {James A.} and Bettina Konte and Claudine Laurent and Phil Lee and Lee, {S. Hong} and Legge, {Sophie E.} and Bernard Lerer and Levy, {Deborah L.} and Liang, {Kung Yee} and Jeffrey Lieberman and Jouko L{\"o}nnqvist and Loughland, {Carmel M.} and Magnusson, {Patrik K E} and Maher, {Brion S.} and Wolfgang Maier and Jacques Mallet and Manuel Mattheisen and Morten Mattingsdal and McCarley, {Robert W.} and Colm McDonald and McIntosh, {Andrew M.} and Sandra Meier and Meijer, {Carin J.} and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Younes Mokrab and Morris, {Derek W.} and Bertram M{\"u}ller-Myhsok and Murphy, {Kieran C.} and Murray, {Robin M.} and Inez Myin-Germeys and Igor Nenadic and Nertney, {Deborah A.} and Gerald Nestadt and Nicodemus, {Kristin K.} and Laura Nisenbaum and Annelie Nordin and Eadbhard O'Callaghan and Colm O'Dushlaine and Oh, {Sang Yun} and Ann Olincy and Line Olsen and O'Neill, {F. Anthony} and {Van Os}, Jim and Christos Pantelis and Papadimitriou, {George N.} and Elena Parkhomenko and Pato, {Michele T.} and Tiina Paunio and Perkins, {Diana O.} and Pers, {Tune H.} and Olli Pietil{\"a}inen and Jonathan Pimm and Pocklington, {Andrew J.} and John Powell and Alkes Price and Pulver, {Ann E.} and Purcell, {Shaun M.} and Digby Quested and Rasmussen, {Henrik B.} and Abraham Reichenberg and Reimers, {Mark A.} and Richards, {Alexander L.} and Roffman, {Joshua L.} and Panos Roussos and Ruderfer, {Douglas M.} and Veikko Salomaa and Sanders, {Alan R.} and Adam Savitz and Ulrich Schall and Schulze, {Thomas G.} and Schwab, {Sibylle G.} and Scolnick, {Edward M.} and Scott, {Rodney J.} and Seidman, {Larry J.} and Jianxin Shi and Silverman, {Jeremy M.} and Smoller, {Jordan W.} and Erik S{\"o}derman and Spencer, {Chris C A} and Stahl, {Eli A.} and Eric Strengman and Jana Strohmaier and Stroup, {T. Scott} and Jaana Suvisaari and Svrakic, {Dragan M.} and Szatkiewicz, {Jin P.} and Srinivas Thirumalai and Tooney, {Paul A.} and Juha Veijola and Visscher, {Peter M.} and John Waddington and Dermot Walsh and Webb, {Bradley T.} and Mark Weiser and Wildenauer, {Dieter B.} and Williams, {Nigel M.} and Stephanie Williams and Witt, {Stephanie H.} and Wolen, {Aaron R.} and Wormley, {Brandon K.} and Wray, {Naomi R.} and Wu, {Jing Qin} and Zai, {Clement C.} and Rolf Adolfsson and Andreassen, {Ole A.} and Blackwood, {Douglas H R} and Elvira Bramon and Buxbaum, {Joseph D.} and Sven Cichon and Collier, {David A.} and Aiden Corvin and Daly, {Mark J.} and Ariel Darvasi and Enrico Domenici and T{\~o}nu Esko and Gejman, {Pablo V.} and Michael Gill and Hugh Gurling and Hultman, {Christina M.} and Nakao Iwata and Jablensky, {Assen V.} and J{\"o}nsson, {Erik G.} and Kendler, {Kenneth S.} and George Kirov and Jo Knight and Levinson, {Douglas F.} and Li, {Qingqin S.} and McCarroll, {Steven A.} and Andrew McQuillin and Moran, {Jennifer L.} and Mowry, {Bryan J.} and N{\"o}then, {Markus M.} and Ophoff, {Roel A.} and Owen, {Michael J.} and Aarno Palotie and Pato, {Carlos N.} and Petryshen, {Tracey L.} and {Psychosis Endophenotypes International Consortium} and {CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium}",

year = "2017",

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day = "1",

doi = "10.1038/ng.3725",

language = "English",

volume = "49",

pages = "27--35",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group - Macmillan Publishers",

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}

Marshall, CR, Howrigan, DP, Merico, D, Thiruvahindrapuram, B, Wu, W, Greer, DS, Antaki, D, Shetty, A, Holmans, PA, Pinto, D, Gujral, M, Brandler, WM, Malhotra, D, Wang, Z, Fuentes Fajarado, KV, Maile, MS, Ripke, S, Agartz, I, Albus, M, Alexander, M, Amin, F, Atkins, J, Bacanu, SA, Belliveau, RA, Bergen, SE, Bertalan, M, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Bulik-Sullivan, B, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Cheng, W, Cloninger, CR, Cohen, D, Cormican, P, Craddock, N, Crespo-Facorro, B, Crowley, JJ, Curtis, D, Davidson, M, Davis, KL, Degenhardt, F, Del Favero, J, DeLisi, LE, Dikeos, D, Dinan, T, Djurovic, S, Donohoe, G, Drapeau, E, Duan, J, Dudbridge, F, Eichhammer, P, Eriksson, J, Escott-Price, V, Essioux, L, Fanous, AH, Farh, KH, Farrell, MS, Frank, J, Franke, L, Freedman, R, Freimer, NB, Friedman, JI, Forstner, AJ, Fromer, M, Genovese, G, Georgieva, L, Gershon, ES, Giegling, I, Giusti-Rodríguez, P, Godard, S, Goldstein, JI, Gratten, J, De Haan, L, Hamshere, ML, Hansen, M, Hansen, T, Haroutunian, V, Hartmann, AM, Henskens, FA, Herms, S, Hirschhorn, JN, Hoffmann, P, Hofman, A, Huang, H, Ikeda, M, Joa, I, Kähler, AK, Kahn, RS, Kalaydjieva, L, Karjalainen, J, Kavanagh, D, Keller, MC, Kelly, BJ, Kennedy, JL, Kim, Y, Knowles, JA, Konte, B, Laurent, C, Lee, P, Lee, SH, Legge, SE, Lerer, B, Levy, DL, Liang, KY, Lieberman, J, Lönnqvist, J, Loughland, CM, Magnusson, PKE, Maher, BS, Maier, W, Mallet, J, Mattheisen, M, Mattingsdal, M, McCarley, RW, McDonald, C, McIntosh, AM, Meier, S, Meijer, CJ, Melle, I, Mesholam-Gately, RI, Metspalu, A, Michie, PT, Milani, L, Milanova, V, Mokrab, Y, Morris, DW, Müller-Myhsok, B, Murphy, KC, Murray, RM, Myin-Germeys, I, Nenadic, I, Nertney, DA, Nestadt, G, Nicodemus, KK, Nisenbaum, L, Nordin, A, O'Callaghan, E, O'Dushlaine, C, Oh, SY, Olincy, A, Olsen, L, O'Neill, FA, Van Os, J, Pantelis, C, Papadimitriou, GN, Parkhomenko, E, Pato, MT, Paunio, T, Perkins, DO, Pers, TH, Pietiläinen, O, Pimm, J, Pocklington, AJ, Powell, J, Price, A, Pulver, AE, Purcell, SM, Quested, D, Rasmussen, HB, Reichenberg, A, Reimers, MA, Richards, AL, Roffman, JL, Roussos, P, Ruderfer, DM, Salomaa, V, Sanders, AR, Savitz, A, Schall, U, Schulze, TG, Schwab, SG, Scolnick, EM, Scott, RJ, Seidman, LJ, Shi, J, Silverman, JM, Smoller, JW, Söderman, E, Spencer, CCA, Stahl, EA, Strengman, E, Strohmaier, J, Stroup, TS, Suvisaari, J, Svrakic, DM, Szatkiewicz, JP, Thirumalai, S, Tooney, PA, Veijola, J, Visscher, PM, Waddington, J, Walsh, D, Webb, BT, Weiser, M, Wildenauer, DB, Williams, NM, Williams, S, Witt, SH, Wolen, AR, Wormley, BK, Wray, NR, Wu, JQ, Zai, CC, Adolfsson, R, Andreassen, OA, Blackwood, DHR, Bramon, E, Buxbaum, JD, Cichon, S, Collier, DA, Corvin, A, Daly, MJ, Darvasi, A, Domenici, E, Esko, T, Gejman, PV, Gill, M, Gurling, H, Hultman, CM, Iwata, N, Jablensky, AV, Jönsson, EG, Kendler, KS, Kirov, G, Knight, J, Levinson, DF, Li, QS, McCarroll, SA, McQuillin, A, Moran, JL, Mowry, BJ, Nöthen, MM, Ophoff, RA, Owen, MJ, Palotie, A, Pato, CN, Petryshen, TL, Psychosis Endophenotypes International Consortium & CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium 2017, 'Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects', Nature Genetics, vol. 49, no. 1, pp. 27-35. https://doi.org/10.1038/ng.3725

TY - JOUR

T1 - Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

AU - Marshall, Christian R.

AU - Howrigan, Daniel P.

AU - Merico, Daniele

AU - Thiruvahindrapuram, Bhooma

AU - Wu, Wenting

AU - Greer, Douglas S.

AU - Antaki, Danny

AU - Shetty, Aniket

AU - Holmans, Peter A.

AU - Pinto, Dalila

AU - Gujral, Madhusudan

AU - Brandler, William M.

AU - Malhotra, Dheeraj

AU - Wang, Zhouzhi

AU - Fuentes Fajarado, Karin V.

AU - Maile, Michelle S.

AU - Ripke, Stephan

AU - Agartz, Ingrid

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Atkins, Joshua

AU - Bacanu, Silviu A.

AU - Belliveau, Richard A.

AU - Bergen, Sarah E.

AU - Bertalan, Marcelo

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Bulik-Sullivan, Brendan

AU - Byerley, William

AU - Cahn, Wiepke

AU - Cai, Guiqing

AU - Cairns, Murray J.

AU - Campion, Dominique

AU - Cantor, Rita M.

AU - Carr, Vaughan J.

AU - Carrera, Noa

AU - Catts, Stanley V.

AU - Chambert, Kimberley D.

AU - Cheng, Wei

AU - Cloninger, C. Robert

AU - Cohen, David

AU - Cormican, Paul

AU - Craddock, Nick

AU - Crespo-Facorro, Benedicto

AU - Crowley, James J.

AU - Curtis, David

AU - Davidson, Michael

AU - Davis, Kenneth L.

AU - Degenhardt, Franziska

AU - Del Favero, Jurgen

AU - DeLisi, Lynn E.

AU - Dikeos, Dimitris

AU - Dinan, Timothy

AU - Djurovic, Srdjan

AU - Donohoe, Gary

AU - Drapeau, Elodie

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AU - Psychosis Endophenotypes International Consortium

AU - CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

AB - Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10-15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10-6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10-5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

UR - http://www.scopus.com/inward/record.url?scp=84997770295&partnerID=8YFLogxK

U2 - 10.1038/ng.3725

DO - 10.1038/ng.3725

M3 - Article

C2 - 27869829

AN - SCOPUS:84997770295

SN - 1061-4036

VL - 49

SP - 27

EP - 35

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Abstract

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