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 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 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,
Wellcome Trust Case-Control Consortium,
Rolf Adolfsson,
Ole A. 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 Noethen,
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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