A contribution of novel CNVs to schizophrenia from a genome-wide study of 41,321 subjects: CNV Analysis Group and the Schizophrenia Working Group of the Psychiatric Genomics Consortium
Authors: Marshall Christian R. , Howrigan Daniel P. , Merico Daniele , Thiruvahindrapuram Bhooma , Wu Wenting , Greer Douglas S. , Antaki Danny , Shetty Aniket , Holmans Peter A. , Pinto Dalila , Gujral Madhusudan , Brandler William M. , Malhotra Dheeraj , Wang Zhouzhi , Fuentes Fajarado Karin V. , Ripke Stephan , Agartz Ingrid , Agerbo Esben , Albus Margot , Alexander Madeline , Amin Farooq , Atkins Joshua , Bacanu Silviu A. , Belliveau Richard A. , Bergen Sarah E. , Bertalan Marcelo , Bevilacqua Elizabeth , Bigdeli Tim B. , Black Donald W. , Bruggeman Richard , Buccola Nancy G. , Buckner Randy L. , Bulik-Sullivan Brendan , Byerley William , Cahn Wiepke , Cai Guiqing , Cairns Murray J. , Campion Dominique , Cantor Rita M. , Carr Vaughan J. , Carrera Noa , Catts Stanley V. , Chambert Kimberley D. , Cheng Wei , Cloninger C. Robert , Cohen David , Cormican Paul , Craddock Nick , Crespo-Facorro Benedicto , Crowley James J. , Curtis David , Davidson Michael , Davis Kenneth L , Degenhardt Franziska , Del Favero Jurgen , DeLisi Lynn E. , Demontis Ditte , Dikeos Dimitris , Dinan Timothy , Djurovic Srdjan , Donohoe Gary , Drapeau Elodie , Duan Jubao , Dudbridge Frank , Eichhammer Peter , Eriksson Johan , Escott-Price Valentina , Essioux Laurent , Fanous Ayman H. , Farh Kai-How , Farrell Martilias S. , Frank Josef , Franke Lude , Freedman Robert , Freimer Nelson B. , Friedman Joseph I. , Forstner Andreas J. , Fromer Menachem , Genovese Giulio , Georgieva Lyudmila , Gershon Elliot S. , Giegling Ina , Giusti-Rodríguez Paola , Godard Stephanie , Goldstein Jacqueline I. , Gratten Jacob , de Haan Lieuwe , Hamshere Marian L. , Hansen Mark , Hansen Thomas , Haroutunian Vahram , Hartmann Annette M. , Henskens Frans A. , Herms Stefan , Hirschhorn Joel N. , Hoffmann Per , Hofman Andrea , Hollegaard Mads V. , Hougaard David M. , Huang Hailiang , Ikeda Masashi , Joa Inge , Anna K Kähler , Kahn René S , Kalaydjieva Luba , Karjalainen Juha , Kavanagh David , Keller Matthew C. , Kelly Brian J. , Kennedy James L. , Kim Yunjung , Knowles James A. , Konte Bettina , Laurent Claudine , Lee Phil , Lee S. Hong , Legge Sophie E. , Lerer Bernard , Levy Deborah L. , Liang Kung-Yee , Lieberman Jeffrey , Lönnqvist Jouko , Loughland Carmel M. , Magnusson Patrik K.E. , Maher Brion S. , Maier Wolfgang , Mallet Jacques , Mattheisen Manuel , Mattingsdal Morten , McCarley Robert W , McDonald Colm , McIntosh Andrew M. , Meier Sandra , Meijer Carin J. , Melle Ingrid , Mesholam-Gately Raquelle I. , Metspalu Andres , Michie Patricia T. , Milani Lili , Milanova Vihra , Mokrab Younes , Morris Derek W. , Mors Ole , Müller-Myhsok Bertram , Murphy Kieran C. , Murray Robin M. , Myin-Germeys Inez , Nenadic Igor , Nertney Deborah A. , Nestadt Gerald , Nicodemus Kristin K. , Nisenbaum Laura , Nordin Annelie , O’ Callaghan Eadbhard , O’ Dushlaine Colm , Oh Sang-Yun , Olincy Ann , Olsen Line , O’ Neill F. Anthony , Van Os Jim , Pantelis Christos , Papadimitriou George N. , Parkhomenko Elena , Pato Michele T. , Paunio Tiina ,   Psychosis Endophenotypes International Consortium, Perkins Diana O. , Pers Tune H. , Pietiläinen Olli , Pimm Jonathan , Pocklington Andrew J. , Powell John , Price Alkes , Pulver Ann E. , Purcell Shaun M. , Quested Digby , Rasmussen Henrik B. , Reichenberg Abraham , Reimers Mark A. , Richards Alexander L. , Roffman Joshua L. , Roussos Panos , Ruderfer Douglas M. , Salomaa Veikko , Sanders Alan R. , Savitz Adam , Schall Ulrich , Schulze Thomas G. , Schwab Sibylle G. , Scolnick Edward M. , Scott Rodney J. , Seidman Larry J. , Shi Jianxin , Silverman Jeremy M. , Smoller Jordan W. , Söderman Erik , Spencer Chris C.A. , Stahl Eli A. , Strengman Eric , Strohmaier Jana , Stroup T. Scott , Suvisaari Jaana , Svrakic Dragan M. , Szatkiewicz Jin P. , Thirumalai Srinivas , Tooney Paul A. , Veijola Juha , Visscher Peter M. , Waddington John , Walsh Dermot , Webb Bradley T. , Weiser Mark , Wildenauer Dieter B. , Williams Nigel M. , Williams Stephanie , Witt Stephanie H. , Wolen Aaron R. , Wormley Brandon K. , Wray Naomi R , Qin Wu Jing , Zai Clement C. ,   Wellcome Trust Case-Control Consortium, Adolfsson Rolf , Andreassen Ole A. , Blackwood Douglas H.R. , Børglum Anders D. , Bramon Elvira , Buxbaum Joseph D. , Cichon Sven , Collier David A. , Corvin Aiden , Daly Mark J. , Darvasi Ariel , Domenici Enrico , Esko Tõnu , Gejman Pablo V. , Gill Michael , Gurling Hugh , Hultman Christina M. , Iwata Nakao , Jablensky Assen V. , Jönsson Erik G , Kendler Kenneth S , Kirov George , Knight Jo , Levinson Douglas F. , Li Qingqin S , McCarroll Steven A , McQuillin Andrew , Moran Jennifer L. , Mortensen Preben B. , Mowry Bryan J. , Nöthen Markus M. , Ophoff Roel A. , Owen Michael J. , Palotie Aarno , Pato Carlos N. , Petryshen Tracey L. , Posthuma Danielle , Rietschel Marcella , Riley Brien P. , Rujescu Dan , Sklar Pamela , Clair David St. , Walters James T.R. , Werge Thomas , Sullivan Patrick F. , O’Donovan Michael C , Scherer Stephen W. , Neale Benjamin M. , Sebat Jonathan 
Published: February 2016

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).