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

Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticle

200 Citations (Scopus)

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 languageEnglish
Pages (from-to)27-35
Number of pages9
JournalNature Genetics
Volume49
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017
Externally publishedYes

Fingerprint

Schizophrenia
Odds Ratio
Genome
Homologous Recombination
Sample Size
Phenotype
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Psychosis Endophenotypes International Consortium, & CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium (2017). Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics, 49(1), 27-35. https://doi.org/10.1038/ng.3725

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. / Psychosis Endophenotypes International Consortium; CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium.

In: Nature Genetics, Vol. 49, No. 1, 01.01.2017, p. 27-35.

Research output: Contribution to journalArticle

Psychosis Endophenotypes International Consortium & CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium 2017, 'Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects', Nature Genetics, vol. 49, no. 1, pp. 27-35. https://doi.org/10.1038/ng.3725
Psychosis Endophenotypes International Consortium, CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nature Genetics. 2017 Jan 1;49(1):27-35. https://doi.org/10.1038/ng.3725
Psychosis Endophenotypes International Consortium ; CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium. / Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. In: Nature Genetics. 2017 ; Vol. 49, No. 1. pp. 27-35.
@article{f10d5905bd6e483faef854b109fe5a14,
title = "Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects",
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.",
author = "{Psychosis Endophenotypes International Consortium} and {CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium} and Marshall, {Christian R.} and Howrigan, {Daniel P.} and Daniele Merico and Bhooma Thiruvahindrapuram and Wenting Wu and Greer, {Douglas S.} and Danny Antaki and Aniket Shetty and Holmans, {Peter A.} and Dalila Pinto and Madhusudan Gujral and Brandler, {William M.} and Dheeraj Malhotra and Zhouzhi Wang and {Fuentes Fajarado}, {Karin V.} and Maile, {Michelle S.} and Stephan Ripke and Ingrid Agartz and Margot Albus and Madeline Alexander and Farooq Amin and Joshua Atkins and Bacanu, {Silviu A.} and Belliveau, {Richard A.} and Bergen, {Sarah E.} and Marcelo Bertalan and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and Brendan Bulik-Sullivan and William Byerley and Wiepke Cahn and Guiqing Cai and Cairns, {Murray J.} and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Catts, {Stanley V.} and Chambert, {Kimberley D.} and Wei Cheng and Cloninger, {C. Robert} and David Cohen and Paul Cormican and Nick Craddock and Benedicto Crespo-Facorro and Younes Mokrab",
year = "2017",
month = "1",
day = "1",
doi = "10.1038/ng.3725",
language = "English",
volume = "49",
pages = "27--35",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

AU - Psychosis Endophenotypes International Consortium

AU - CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium

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 - Mokrab, Younes

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

UR - http://www.scopus.com/inward/citedby.url?scp=84997770295&partnerID=8YFLogxK

U2 - 10.1038/ng.3725

DO - 10.1038/ng.3725

M3 - Article

VL - 49

SP - 27

EP - 35

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -