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A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects

By 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, Stephan Ripke, Ingrid Agartz, Esben Agerbo, 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, Ditte Demontis, 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 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, Mads V Hollegaard, David M Hougaard, Hailiang Huang, Masashi Ikeda, Inge Joa, K Kähler Anna, 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, Sang 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, Ole Mors, Bertram Muller-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, T. Paunio, Psychosis Endophenotypes International Consortium, 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 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 CA Spencer, Eli A. Stahl, Eric Strengman, Jana Strohmaier, T Scott Stroup, J. Suvisaari, Dragan M Svrakic, Jin P Szatkiewicz, Srinivas Thirumalai, Paul A Tooney, Juha Veijola, Peter M Visscher, John Waddington, Dermot Walsh, Bradley Todd 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, Wellcome Trust Case-Control Consortium, Rolf Adolfsson, Ole Andreassen, Douglas HR Blackwood, Anders Børglum, Elvira Bramon, Joseph D. Buxbaum, Sven Cichon, David A. Collier, Aiden Corvin, Mark 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, Kirov George, Jo Knight, Douglas F Levinson, Qingqin S Li, Steven A McCarroll, Andrew McQuillin, Jennifer L. Moran, Preben Bo Mortensen, Bryan J Mowry, Markus M Nothen, Roel A. Ophoff, Michael J Owen, Aarno Palotie, Carlos Pato, Tracey L Petryshen, Danielle Posthuma, Marcella Rietschel, Brien P Riley, Dan Rujescu, Pamela Sklar, David St. Clair, James TR Walters, Thomas Werge, Patrick F Sullivan, Michael C O’Donovan, Stephen W. Scherer, Benjamin M. Neale, Jonathan Sebat

Posted 23 Feb 2016
bioRxiv DOI: 10.1101/040493 (published DOI: 10.1038/ng.3725)

Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).

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