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

Citation:

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 Fuentes V 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, Robert C 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, Andre A 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, Yun Jung Kim, James A Knowles, Bettina Konte, Claudine Laurent, Phil Lee, Hong S Lee, Sophie E Legge, Bernard Lerer, Deborah L Levy, Kung-Yee Liang, Jeffrey Lieberman, Jouko Lönnqvist, Carmel M Loughland, Patrik KE 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, Anthony F 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 CA Spencer, Eli A Stahl, Eric Strengman, Jana Strohmaier, Scott T 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 HR 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, 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, and Jonathan Sebat. 2017. “Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.” Nat Genet, 49, 1, Pp. 27-35.

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.