Rare chromosomal deletions and duplications increase risk of schizophrenia

Jennifer L. Stone; Michael C. O'Donovan; Hugh Gurling; George K. Kirov; Douglas H.R. Blackwood; Aiden Corvin; Nick J. Craddock; Michael Gill; Christina M. Hultman; Paul Lichtenstein; Andrew McQuillin; Carlos N. Pato; Douglas M. Ruderfer; Michael J. Owen; David St Clair; Patrick F. Sullivan; Pamela Sklar; Shaun M. Purcell; Joshua Korn; Stuart Macgregor; Derek W. Morris; Colm T. O'Dushlaine; Mark J. Daly; Peter M. Visscher; Peter A. Holmans; Edward M. Scolnick; Nigel M. Williams; Lucy Georgieva; Ivan Nikolov; N. Norton; H. Williams; Draga Toncheva; Vihra Milanova; Emma F. Thelander; Elaine Kenny; John L. Waddington; Khalid Choudhury; Susmita Datta; Jonathan Pimm; Srinivasa Thirumalai; Vinay Puri; Robert Krasucki; Jacob Lawrence; Digby Quested; Nicholas Bass; David Curtis; Caroline Crombie; Gillian Fraser; Soh Leh Kwan; Nicholas Walker; Walter J. Muir; Kevin A. McGhee; Ben Pickard; Pat Malloy; Alan W. Maclean; Margaret Van Beck; Michele T. Pato; Helena Medeiros; Frank Middleton; Celia Carvalho; Christopher Morley; Ayman Fanous; David Conti; James A. Knowles; Carlos Paz Ferreira; Antonio Macedo; M. Helena Azevedo; Steve A. McCarroll; Kimberly Chambert; Casey Gates; Stacey B. Gabriel; Scott Mahon; Kristen Ardlie

doi:10.1038/nature07239

Rare chromosomal deletions and duplications increase risk of schizophrenia

Jennifer L. Stone, Michael C. O'Donovan, Hugh Gurling, George K. Kirov, Douglas H.R. Blackwood, Aiden Corvin, Nick J. Craddock, Michael Gill, Christina M. Hultman, Paul Lichtenstein, Andrew McQuillin, Carlos N. Pato, Douglas M. Ruderfer, Michael J. Owen, David St Clair, Patrick F. Sullivan, Pamela Sklar, Shaun M. Purcell, Joshua Korn, Stuart MacgregorDerek W. Morris, Colm T. O'Dushlaine, Mark J. Daly, Peter M. Visscher, Peter A. Holmans, Edward M. Scolnick, Nigel M. Williams, Lucy Georgieva, Ivan Nikolov, N. Norton, H. Williams, Draga Toncheva, Vihra Milanova, Emma F. Thelander, Elaine Kenny, John L. Waddington, Khalid Choudhury, Susmita Datta, Jonathan Pimm, Srinivasa Thirumalai, Vinay Puri, Robert Krasucki, Jacob Lawrence, Digby Quested, Nicholas Bass, David Curtis, Caroline Crombie, Gillian Fraser, Soh Leh Kwan, Nicholas Walker, Walter J. Muir, Kevin A. McGhee, Ben Pickard, Pat Malloy, Alan W. Maclean, Margaret Van Beck, Michele T. Pato, Helena Medeiros, Frank Middleton, Celia Carvalho, Christopher Morley, Ayman Fanous, David Conti, James A. Knowles, Carlos Paz Ferreira, Antonio Macedo, M. Helena Azevedo, Steve A. McCarroll, Kimberly Chambert, Casey Gates, Stacey B. Gabriel, Scott Mahon, Kristen Ardlie

Cancer Biology

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Abstract

Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

Original language	English (US)
Pages (from-to)	237-241
Number of pages	5
Journal	Nature
Volume	455
Issue number	7210
DOIs	https://doi.org/10.1038/nature07239
State	Published - Sep 2008

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Stone, J. L., O'Donovan, M. C., Gurling, H., Kirov, G. K., Blackwood, D. H. R., Corvin, A., Craddock, N. J., Gill, M., Hultman, C. M., Lichtenstein, P., McQuillin, A., Pato, C. N., Ruderfer, D. M., Owen, M. J., St Clair, D., Sullivan, P. F., Sklar, P., Purcell, S. M., Korn, J., ... Ardlie, K. (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455(7210), 237-241. https://doi.org/10.1038/nature07239

Stone, JL, O'Donovan, MC, Gurling, H, Kirov, GK, Blackwood, DHR, Corvin, A, Craddock, NJ, Gill, M, Hultman, CM, Lichtenstein, P, McQuillin, A, Pato, CN, Ruderfer, DM, Owen, MJ, St Clair, D, Sullivan, PF, Sklar, P, Purcell, SM, Korn, J, Macgregor, S, Morris, DW, O'Dushlaine, CT, Daly, MJ, Visscher, PM, Holmans, PA, Scolnick, EM, Williams, NM, Georgieva, L, Nikolov, I, Norton, N, Williams, H, Toncheva, D, Milanova, V, Thelander, EF, Kenny, E, Waddington, JL, Choudhury, K, Datta, S, Pimm, J, Thirumalai, S, Puri, V, Krasucki, R, Lawrence, J, Quested, D, Bass, N, Curtis, D, Crombie, C, Fraser, G, Leh Kwan, S, Walker, N, Muir, WJ, McGhee, KA, Pickard, B, Malloy, P, Maclean, AW, Van Beck, M, Pato, MT, Medeiros, H, Middleton, F, Carvalho, C, Morley, C, Fanous, A, Conti, D, Knowles, JA, Paz Ferreira, C, Macedo, A, Helena Azevedo, M, McCarroll, SA, Chambert, K, Gates, C, Gabriel, SB, Mahon, S & Ardlie, K 2008, 'Rare chromosomal deletions and duplications increase risk of schizophrenia', Nature, vol. 455, no. 7210, pp. 237-241. https://doi.org/10.1038/nature07239

@article{2d0e4533a0514abba0be4b7fcbab0e6e,

title = "Rare chromosomal deletions and duplications increase risk of schizophrenia",

abstract = "Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.",

author = "Stone, {Jennifer L.} and O'Donovan, {Michael C.} and Hugh Gurling and Kirov, {George K.} and Blackwood, {Douglas H.R.} and Aiden Corvin and Craddock, {Nick J.} and Michael Gill and Hultman, {Christina M.} and Paul Lichtenstein and Andrew McQuillin and Pato, {Carlos N.} and Ruderfer, {Douglas M.} and Owen, {Michael J.} and {St Clair}, David and Sullivan, {Patrick F.} and Pamela Sklar and Purcell, {Shaun M.} and Joshua Korn and Stuart Macgregor and Morris, {Derek W.} and O'Dushlaine, {Colm T.} and Daly, {Mark J.} and Visscher, {Peter M.} and Holmans, {Peter A.} and Scolnick, {Edward M.} and Williams, {Nigel M.} and Lucy Georgieva and Ivan Nikolov and N. Norton and H. Williams and Draga Toncheva and Vihra Milanova and Thelander, {Emma F.} and Elaine Kenny and Waddington, {John L.} and Khalid Choudhury and Susmita Datta and Jonathan Pimm and Srinivasa Thirumalai and Vinay Puri and Robert Krasucki and Jacob Lawrence and Digby Quested and Nicholas Bass and David Curtis and Caroline Crombie and Gillian Fraser and {Leh Kwan}, Soh and Nicholas Walker and Muir, {Walter J.} and McGhee, {Kevin A.} and Ben Pickard and Pat Malloy and Maclean, {Alan W.} and {Van Beck}, Margaret and Pato, {Michele T.} and Helena Medeiros and Frank Middleton and Celia Carvalho and Christopher Morley and Ayman Fanous and David Conti and Knowles, {James A.} and {Paz Ferreira}, Carlos and Antonio Macedo and {Helena Azevedo}, M. and McCarroll, {Steve A.} and Kimberly Chambert and Casey Gates and Gabriel, {Stacey B.} and Scott Mahon and Kristen Ardlie",

note = "Funding Information: Acknowledgements We thank the patients and families who contributed their time and DNA to these studies, and also D. Altshuler and members of the Medical and Population Genetics group at the Broad Institute of Harvard and Massachusetts Institute of Technology for valuable discussion. The group at the Stanley Center for Psychiatric Research at the Broad Institute was supported by the Stanley Medical Research Institute (E.M.S.), the Sylvan C. Herman Foundation (E.M.S.), and MH071681 (P.S.). The Cardiff University group was supported by a Medical Research Council (UK) Programme grant and the National Institutes of Mental Health (USA) (CONTE: 2 P50 MH066392-05A1). The group at Karolinska Institutet was supported by the Swedish Council for Working Life and Social Research (FO 184/2000; 2001-2368). The Massachusetts General Hospital group was supported by the Stanley Medical Research Institute (P.S.), MH071681 (P.S.) and a Narsad Young Investigator Award (S.P.). The group at the Queensland Institute of Medical Research was supported by the Australian National Health and Medical Research Council. The Trinity College Dublin group was supported by Science Foundation Ireland, the Health Research Board (Ireland), the Stanley Medical Research Institute and the Wellcome Trust; Irish controls were supplied by J. McPartlin from the Trinity College Biobank. The work at the University of Aberdeen was partly funded by GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. The University College London clinical and control samples were collected with support from the Neuroscience Research Charitable Trust, the Camden and Islington Mental Health and Social Care Trust, East London and City Mental Heath Trust, the West Berkshire NHS Trust, the West London Mental Health Trust, Oxfordshire and Buckinghamshire Mental Health Partnership NHS Trust, South Essex Partnership NHS Foundation Trust, Gloucestershire Partnership NHS Foundation Trust, Mersey Care NHS Trust, Hampshire Partnership NHS Trust and the North East London Mental Health Trust. The collection of the University of Edinburgh cohort was supported by grants from the Wellcome Trust, London, and the Chief Scientist Office of the Scottish Executive. The group at the University of North Carolina, Chapel Hill, was supported by MH074027, MH077139 and MH080403, the Sylvan C. Herman Foundation (P.F.S.) and the Stanley Medical Research Institute (P.F.S.) The group at the University of Southern California thanks the patients and their families for their collaboration, and acknowledges the support of the National Institutes of Mental Health and the Department of Veterans Affairs.",

year = "2008",

month = sep,

doi = "10.1038/nature07239",

language = "English (US)",

volume = "455",

pages = "237--241",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7210",

}

TY - JOUR

T1 - Rare chromosomal deletions and duplications increase risk of schizophrenia

AU - Stone, Jennifer L.

AU - O'Donovan, Michael C.

AU - Gurling, Hugh

AU - Kirov, George K.

AU - Blackwood, Douglas H.R.

AU - Corvin, Aiden

AU - Craddock, Nick J.

AU - Gill, Michael

AU - Hultman, Christina M.

AU - Lichtenstein, Paul

AU - McQuillin, Andrew

AU - Pato, Carlos N.

AU - Ruderfer, Douglas M.

AU - Owen, Michael J.

AU - St Clair, David

AU - Sullivan, Patrick F.

AU - Sklar, Pamela

AU - Purcell, Shaun M.

AU - Korn, Joshua

AU - Macgregor, Stuart

AU - Morris, Derek W.

AU - O'Dushlaine, Colm T.

AU - Daly, Mark J.

AU - Visscher, Peter M.

AU - Holmans, Peter A.

AU - Scolnick, Edward M.

AU - Williams, Nigel M.

AU - Georgieva, Lucy

AU - Nikolov, Ivan

AU - Norton, N.

AU - Williams, H.

AU - Toncheva, Draga

AU - Milanova, Vihra

AU - Thelander, Emma F.

AU - Kenny, Elaine

AU - Waddington, John L.

AU - Choudhury, Khalid

AU - Datta, Susmita

AU - Pimm, Jonathan

AU - Thirumalai, Srinivasa

AU - Puri, Vinay

AU - Krasucki, Robert

AU - Lawrence, Jacob

AU - Quested, Digby

AU - Bass, Nicholas

AU - Curtis, David

AU - Crombie, Caroline

AU - Fraser, Gillian

AU - Leh Kwan, Soh

AU - Walker, Nicholas

AU - Muir, Walter J.

AU - McGhee, Kevin A.

AU - Pickard, Ben

AU - Malloy, Pat

AU - Maclean, Alan W.

AU - Van Beck, Margaret

AU - Pato, Michele T.

AU - Medeiros, Helena

AU - Middleton, Frank

AU - Carvalho, Celia

AU - Morley, Christopher

AU - Fanous, Ayman

AU - Conti, David

AU - Knowles, James A.

AU - Paz Ferreira, Carlos

AU - Macedo, Antonio

AU - Helena Azevedo, M.

AU - McCarroll, Steve A.

AU - Chambert, Kimberly

AU - Gates, Casey

AU - Gabriel, Stacey B.

AU - Mahon, Scott

AU - Ardlie, Kristen

N1 - Funding Information: Acknowledgements We thank the patients and families who contributed their time and DNA to these studies, and also D. Altshuler and members of the Medical and Population Genetics group at the Broad Institute of Harvard and Massachusetts Institute of Technology for valuable discussion. The group at the Stanley Center for Psychiatric Research at the Broad Institute was supported by the Stanley Medical Research Institute (E.M.S.), the Sylvan C. Herman Foundation (E.M.S.), and MH071681 (P.S.). The Cardiff University group was supported by a Medical Research Council (UK) Programme grant and the National Institutes of Mental Health (USA) (CONTE: 2 P50 MH066392-05A1). The group at Karolinska Institutet was supported by the Swedish Council for Working Life and Social Research (FO 184/2000; 2001-2368). The Massachusetts General Hospital group was supported by the Stanley Medical Research Institute (P.S.), MH071681 (P.S.) and a Narsad Young Investigator Award (S.P.). The group at the Queensland Institute of Medical Research was supported by the Australian National Health and Medical Research Council. The Trinity College Dublin group was supported by Science Foundation Ireland, the Health Research Board (Ireland), the Stanley Medical Research Institute and the Wellcome Trust; Irish controls were supplied by J. McPartlin from the Trinity College Biobank. The work at the University of Aberdeen was partly funded by GlaxoSmithKline and Generation Scotland, Genetics Health Initiative. The University College London clinical and control samples were collected with support from the Neuroscience Research Charitable Trust, the Camden and Islington Mental Health and Social Care Trust, East London and City Mental Heath Trust, the West Berkshire NHS Trust, the West London Mental Health Trust, Oxfordshire and Buckinghamshire Mental Health Partnership NHS Trust, South Essex Partnership NHS Foundation Trust, Gloucestershire Partnership NHS Foundation Trust, Mersey Care NHS Trust, Hampshire Partnership NHS Trust and the North East London Mental Health Trust. The collection of the University of Edinburgh cohort was supported by grants from the Wellcome Trust, London, and the Chief Scientist Office of the Scottish Executive. The group at the University of North Carolina, Chapel Hill, was supported by MH074027, MH077139 and MH080403, the Sylvan C. Herman Foundation (P.F.S.) and the Stanley Medical Research Institute (P.F.S.) The group at the University of Southern California thanks the patients and their families for their collaboration, and acknowledges the support of the National Institutes of Mental Health and the Department of Veterans Affairs.

PY - 2008/9

Y1 - 2008/9

N2 - Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

AB - Schizophrenia is a severe mental disorder marked by hallucinations, delusions, cognitive deficits and apathy, with a heritability estimated at 73-90% (ref. 1). Inheritance patterns are complex, and the number and type of genetic variants involved are not understood. Copy number variants (CNVs) have been identified in individual patients with schizophrenia and also in neurodevelopmental disorders, but large-scale genome-wide surveys have not been performed. Here we report a genome-wide survey of rare CNVs in 3,391 patients with schizophrenia and 3,181 ancestrally matched controls, using high-density microarrays. For CNVs that were observed in less than 1% of the sample and were more than 100 kilobases in length, the total burden is increased 1.15-fold in patients with schizophrenia in comparison with controls. This effect was more pronounced for rarer, single-occurrence CNVs and for those that involved genes as opposed to those that did not. As expected, deletions were found within the region critical for velo-cardio-facial syndrome, which includes psychotic symptoms in 30% of patients. Associations with schizophrenia were also found for large deletions on chromosome 15q13.3 and 1q21.1. These associations have not previously been reported, and they remained significant after genome-wide correction. Our results provide strong support for a model of schizophrenia pathogenesis that includes the effects of multiple rare structural variants, both genome-wide and at specific loci.

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DO - 10.1038/nature07239

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C2 - 18668038

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VL - 455

SP - 237

EP - 241

JO - Nature

JF - Nature

IS - 7210

ER -

Rare chromosomal deletions and duplications increase risk of schizophrenia

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