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 | |
Publication status | Published - 1 Jan 2017 |
Externally published | Yes |
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In: Nature Genetics, Vol. 49, No. 1, 01.01.2017, p. 27-35.
Research output: Contribution to journal › Article › Research › peer-review
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 D.
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
AU - Duan, Jubao
AU - Dudbridge, Frank
AU - Eichhammer, Peter
AU - Eriksson, Johan Gunnar
AU - Escott-Price, Valentina
AU - Essioux, Laurent
AU - Fanous, Ayman H.
AU - Farh, Kai How
AU - Farrell, Martilias S.
AU - Frank, Josef
AU - Franke, Lude
AU - Freedman, Robert R.
AU - Freimer, Nelson B.
AU - Friedman, Joseph I.
AU - Forstner, Andreas J.
AU - Fromer, Menachem
AU - Genovese, Giulio
AU - Georgieva, Lyudmila
AU - Gershon, Elliot S.
AU - Giegling, Ina
AU - Giusti-Rodríguez, Paola
AU - Godard, Stephanie
AU - Goldstein, Jacqueline I.
AU - Gratten, Jacob
AU - De Haan, Lieuwe
AU - Hamshere, Marian L
AU - Hansen, Mark
AU - Hansen, Thomas W
AU - Haroutunian, Vahram
AU - Hartmann, Annette M.
AU - Henskens, Frans A.
AU - Herms, Stefan
AU - Hirschhorn, Joel N
AU - Hoffmann, Per
AU - Hofman, Andrea
AU - Huang, Hailiang
AU - Ikeda, Masashi
AU - Joa, Inge
AU - Kähler, Anna K.
AU - Kahn, René S.
AU - Kalaydjieva, Luba
AU - Karjalainen, Juha
AU - Kavanagh, David
AU - Keller, Matthew C.
AU - Kelly, Brian J.
AU - Kennedy, James L.
AU - Kim, Yunjung
AU - Knowles, James A.
AU - Konte, Bettina
AU - Laurent, Claudine
AU - Lee, Phil Hyoun
AU - Lee, S. Hong
AU - Legge, Sophie E.
AU - Lerer, Bernard
AU - Levy, Deborah L.
AU - Liang, Kung Yee
AU - Lieberman, Jeffrey
AU - Lönnqvist, Jouko
AU - Loughland, Carmel M.
AU - Magnusson, Patrik K.E.
AU - Maher, Brion S.
AU - Maier, Wolfgang
AU - Mallet, Jacques
AU - Mattheisen, Manuel
AU - Mattingsdal, Morten
AU - McCarley, Robert W.
AU - McDonald, Colm D
AU - McIntosh, Andrew M.
AU - Meier, Sandra
AU - Meijer, Carin J.
AU - Melle, Ingrid
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T.
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mokrab, Younes
AU - Morris, Derek W
AU - Müller-Myhsok, Bertram
AU - Murphy, Kieran C.
AU - Murray, Robin MacGregor
AU - Myin-Germeys, Inez
AU - Nenadic, Igor
AU - Nertney, Deborah A
AU - Nestadt, Gerald
AU - Nicodemus, Kristin K.
AU - Nisenbaum, Laura K
AU - Nordin, Annelie
AU - O'Callaghan, Eadbhard
AU - O'Dushlaine, Colm
AU - Oh, Sang Yun
AU - Olincy, Ann
AU - Olsen, Line
AU - O'Neill, F. Anthony
AU - Van Os, Jim
AU - Pantelis, Christos
AU - Papadimitriou, George N.
AU - Parkhomenko, Elena
AU - Pato, Michele T.
AU - Paunio, Tiina
AU - Perkins, Diana O.
AU - Pers, Tune H
AU - Pietiläinen, Olli
AU - Pimm, Jonathan
AU - Pocklington, Andrew J.
AU - Powell, John
AU - Price, Alkes
AU - Pulver, Ann E.
AU - Purcell, Shaun M.
AU - Quested, Digby
AU - Rasmussen, Henrik B.
AU - Reichenberg, Abraham
AU - Reimers, Mark A.
AU - Richards, Alexander L.
AU - Roffman, Joshua L.
AU - Roussos, Panos
AU - Ruderfer, Douglas M.
AU - Salomaa, Veikko
AU - Sanders, Alan R.
AU - Savitz, Adam
AU - Schall, Ulrich
AU - Schulze, Thomas G.
AU - Schwab, Sibylle G.
AU - Scolnick, Edward M.
AU - Scott, Rodney J
AU - Seidman, Larry J.
AU - Shi, Jianxin
AU - Silverman, Jeremy M.
AU - Smoller, Jordan W.
AU - Söderman, Erik
AU - Spencer, Chris C.A.
AU - Stahl, Eli A
AU - Strengman, Eric
AU - Strohmaier, Jana
AU - Stroup, T. Scott
AU - Suvisaari, Jaana
AU - Svrakic, Dragan M.
AU - Szatkiewicz, Jin P.
AU - Thirumalai, Srinivas
AU - Tooney, Paul A
AU - Veijola, Juha
AU - Visscher, Peter M
AU - Waddington, John L
AU - Walsh, Dermot
AU - Webb, Bradley T.
AU - Weiser, Mark
AU - Wildenauer, Dieter B.
AU - Williams, Nigel M A
AU - Williams, Stephanie
AU - Witt, Stephanie H
AU - Wolen, Aaron R.
AU - Wormley, Brandon K.
AU - Wray, Naomi R.
AU - Wu, Jing Qin
AU - Zai, Clement C.
AU - Adolfsson, Rolf
AU - Andreassen, Ole A.
AU - Blackwood, Douglas H.R.
AU - Bramon, Elvira
AU - Buxbaum, Joseph D.
AU - Cichon, Sven
AU - Collier, David Andrew
AU - Corvin, Aiden
AU - Daly, Mark J
AU - Darvasi, Ariel
AU - Domenici, Enrico
AU - Esko, Tõnu
AU - Gejman, Pablo V.
AU - Gill, Michael
AU - Gurling, Hugh
AU - Hultman, Christina M.
AU - Iwata, Nakao
AU - Jablensky, Assen V.
AU - Jönsson, Erik G.
AU - Kendler, Kenneth S.
AU - Kirov, George
AU - Knight, Jo
AU - Levinson, Douglas F.
AU - Li, Qingqin S.
AU - McCarroll, Steven A.
AU - McQuillin, Andrew
AU - Moran, Jennifer L.
AU - Mowry, Bryan J
AU - Nöthen, Markus M.
AU - Ophoff, Roel A.
AU - Palotie, Aarno
AU - Pato, Carlos N.
AU - Scherer, Stephen W.
AU - Neale, Benjamin M
AU - Sebat, Jonathan
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
AN - SCOPUS:84997770295
SN - 1061-4036
VL - 49
SP - 27
EP - 35
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -