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

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 A. Bacanu; Richard A. Belliveau; Sarah E. Bergen; Marcelo Ertalan; 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; Inez Myin-Germeys; Jim Van Os; CNV; Schizophrenia Working Group; Psychosis Endophenotypes

doi:10.1038/ng.3725

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

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 AlexanderFarooq Amin, Joshua Atkins, Silviu A. Bacanu, Richard A. Belliveau, Sarah E. Bergen, Marcelo Ertalan, 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, Inez Myin-Germeys, Jim Van Os, CNV, Schizophrenia Working Group, Psychosis Endophenotypes

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › 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 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 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	https://doi.org/10.1038/ng.3725
Publication status	Published - Jan 2017

Keywords

GENE
16P11.2
AUTISM
RISK
CNVS
REARRANGEMENTS
DUPLICATIONS
PHENOTYPES
DISORDERS
MUTATIONS

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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., Albus, M., ... Psychosis Endophenotypes (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

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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 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 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 = "GENE, 16P11.2, AUTISM, RISK, CNVS, REARRANGEMENTS, DUPLICATIONS, PHENOTYPES, DISORDERS, MUTATIONS",

author = "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 Bacanu, {Silviu A.} and Belliveau, {Richard A.} and Bergen, {Sarah E.} and Marcelo Ertalan 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 Inez Myin-Germeys and {Van Os}, Jim and CNV and {Schizophrenia Working Group} and {Psychosis Endophenotypes}",

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month = jan,

doi = "10.1038/ng.3725",

language = "English",

volume = "49",

pages = "27--35",

journal = "Nature Genetics",

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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, SA, Belliveau, RA, Bergen, SE, Ertalan, M, Bevilacqua, E, Bigdeli, TB, Black, DW, Bruggeman, R, Buccola, NG, Buckner, RL, Bulik-Sullivan, B, Byerley, W, Cahn, W, Cai, G, Cairns, MJ, Campion, D, Cantor, RM, Carr, VJ, Carrera, N, Catts, SV, Chambert, KD, Cheng, W, Cloninger, CR, Cohen, D, Cormican, P, Myin-Germeys, I, Van Os, J, CNV, Schizophrenia Working Group & Psychosis Endophenotypes 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

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 - 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 A.

AU - Belliveau, Richard A.

AU - Bergen, Sarah E.

AU - Ertalan, 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 - Myin-Germeys, Inez

AU - Van Os, Jim

AU - CNV

AU - Schizophrenia Working Group

AU - Psychosis Endophenotypes

PY - 2017/1

Y1 - 2017/1

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 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 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 x 10(-15)), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 x 10(-6)). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 x 10(-11)) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 x 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 - GENE

KW - 16P11.2

KW - AUTISM

KW - RISK

KW - CNVS

KW - REARRANGEMENTS

KW - DUPLICATIONS

KW - PHENOTYPES

KW - DISORDERS

KW - MUTATIONS

U2 - 10.1038/ng.3725

DO - 10.1038/ng.3725

M3 - Article

C2 - 27869829

SN - 1061-4036

VL - 49

SP - 27

EP - 35

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -