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

Psychosis Endophenotypes International Consortium; 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; Michelle S Maile; Stephan Ripke; Ingrid Agartz; Margot Albus; Madeline Alexander; Farooq Amin; Joshua Atkins; Silviu-Alin 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 K Bulik-Sullivan; William F 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-Tzu Cheng; C Robert Cloninger; David J Cohen; Paul Cormican; Andrew McIntosh; Kristin Nicodemus; Douglas H R Blackwood

doi:10.1038/ng.3725

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

Psychosis Endophenotypes International Consortium, 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, Michelle S Maile, Stephan Ripke, Ingrid Agartz, Margot AlbusMadeline Alexander, Farooq Amin, Joshua Atkins, Silviu-Alin 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 K Bulik-Sullivan, William F 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-Tzu Cheng, C Robert Cloninger, David J Cohen, Paul Cormican, Andrew McIntosh, Kristin Nicodemus, Douglas H R Blackwood

Research output: Contribution to journal › Article › peer-review

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
Early online date	21 Nov 2016
DOIs	https://doi.org/10.1038/ng.3725
Publication status	Published - 11 Jul 2017

Keywords

Case-Control Studies
DNA Copy Number Variations
Female
Genetic Loci
Genetic Markers
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Risk Factors
Schizophrenia
Comparative Study
Journal Article

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Psychosis Endophenotypes International Consortium, Marshall, C. R., Howrigan, D. P., Merico, D., Thiruvahindrapuram, B., Wu, W., Greer, D. S., Antaki, D., Shetty, A., Holmans, P. A., Pinto, D., Gujral, M., Brandler, W. M., Malhotra, D., Wang, Z., Fajarado, K. V. F., Maile, M. S., Ripke, S., Agartz, I., ... Blackwood, D. H. R. (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

Psychosis Endophenotypes International Consortium ; 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 ; Fajarado, Karin V Fuentes ; Maile, Michelle S ; Ripke, Stephan ; Agartz, Ingrid ; Albus, Margot ; Alexander, Madeline ; Amin, Farooq ; Atkins, Joshua ; Bacanu, Silviu-Alin ; 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 K ; Byerley, William F ; 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-Tzu ; Cloninger, C Robert ; Cohen, David J ; Cormican, Paul ; McIntosh, Andrew ; Nicodemus, Kristin ; Blackwood, Douglas H R. / 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{edbc358eb91244208c269ab63d8ac8fb,

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.",

keywords = "Case-Control Studies, DNA Copy Number Variations, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Risk Factors, Schizophrenia, Comparative Study, Journal Article",

author = "{Psychosis Endophenotypes International 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 Fajarado, {Karin V Fuentes} and Maile, {Michelle S} and Stephan Ripke and Ingrid Agartz and Margot Albus and Madeline Alexander and Farooq Amin and Joshua Atkins and Silviu-Alin Bacanu 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 Bulik-Sullivan, {Brendan K} and Byerley, {William F} 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-Tzu Cheng and Cloninger, {C Robert} and Cohen, {David J} and Paul Cormican and Andrew McIntosh and Kristin Nicodemus and Blackwood, {Douglas H R}",

year = "2017",

month = jul,

day = "11",

doi = "10.1038/ng.3725",

language = "English",

volume = "49",

pages = "27--35",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

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Psychosis Endophenotypes International Consortium, Marshall, CR, Howrigan, DP, Merico, D, Thiruvahindrapuram, B, Wu, W, Greer, DS, Antaki, D, Shetty, A, Holmans, PA, Pinto, D, Gujral, M, Brandler, WM, Malhotra, D, Wang, Z, Fajarado, KVF, Maile, MS, Ripke, S, Agartz, I, Albus, M, Alexander, M, Amin, F, Atkins, J, Bacanu, S-A, Belliveau, RA, Bergen, SE, Bertalan, M, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Bulik-Sullivan, BK, Byerley, WF, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Cheng, W-T, Cloninger, CR, Cohen, DJ, Cormican, P, McIntosh, A , Nicodemus, K & Blackwood, DHR 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

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. / Psychosis Endophenotypes International Consortium; 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; Fajarado, Karin V Fuentes; Maile, Michelle S; Ripke, Stephan; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amin, Farooq; Atkins, Joshua; Bacanu, Silviu-Alin; 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 K; Byerley, William F; 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-Tzu; Cloninger, C Robert; Cohen, David J; Cormican, Paul; McIntosh, Andrew ; Nicodemus, Kristin; Blackwood, Douglas H R.

In: Nature Genetics, Vol. 49, No. 1, 11.07.2017, p. 27-35.

Research output: Contribution to journal › Article › peer-review

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 - 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 - Fajarado, Karin V Fuentes

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-Alin

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 K

AU - Byerley, William F

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-Tzu

AU - Cloninger, C Robert

AU - Cohen, David J

AU - Cormican, Paul

AU - McIntosh, Andrew

AU - Nicodemus, Kristin

AU - Blackwood, Douglas H R

PY - 2017/7/11

Y1 - 2017/7/11

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.

KW - Case-Control Studies

KW - DNA Copy Number Variations

KW - Female

KW - Genetic Loci

KW - Genetic Markers

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Male

KW - Risk Factors

KW - Schizophrenia

KW - Comparative Study

KW - Journal Article

U2 - 10.1038/ng.3725

DO - 10.1038/ng.3725

M3 - Article

C2 - 27869829

VL - 49

SP - 27

EP - 35

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -

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

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