Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Shaun M. Purcell; Naomi R. Wray; Jennifer L. Stone; Peter M. Visscher; Michael C. O'Donovan; Patrick F. Sullivan; Douglas M. Ruderfer; Andrew McQuillin; Derek W. Morris; Colm T. Oĝdushlaine; Aiden Corvin; Peter A. Holmans; Michael C. Oĝdonovan; Stuart MacGregor; Hugh Gurling; Douglas H.R. Blackwood; Nick J. Craddock; Michael Gill; Christina M. Hultman; George K. Kirov; Paul Lichtenstein; Walter J. Muir; Michael J. Owen; Carlos N. Pato; Edward M. Scolnick; David St Clair; Nigel M. Williams; Lyudmila Georgieva; Ivan Nikolov; N. Norton; H. Williams; Draga Toncheva; Vihra Milanova; Emma F. Thelander; Colm T. O'Dushlaine; Elaine Kenny; Emma M. Quinn; Khalid Choudhury; Susmita Datta; Jonathan Pimm; Srinivasa Thirumalai; Vinay Puri; Robert Krasucki; Jacob Lawrence; Digby Quested; Nicholas Bass; Caroline Crombie; Gillian Fraser; Soh Leh Kuan; Nicholas Walker; 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; Andrew N. Kirby; Manuel A.R. Ferreira; Mark J. Daly; Kimberly Chambert; Finny Kuruvilla; Stacey B. Gabriel; Kristin Ardlie; Jennifer L. Moran; Pamela Sklar

doi:10.1038/nature08185

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Shaun M. Purcell, Naomi R. Wray, Jennifer L. Stone, Peter M. Visscher, Michael C. O'Donovan, Patrick F. Sullivan, Douglas M. Ruderfer, Andrew McQuillin, Derek W. Morris, Colm T. Oĝdushlaine, Aiden Corvin, Peter A. Holmans, Michael C. Oĝdonovan, Stuart MacGregor, Hugh Gurling, Douglas H.R. Blackwood, Nick J. Craddock, Michael Gill, Christina M. Hultman, George K. KirovPaul Lichtenstein, Walter J. Muir, Michael J. Owen, Carlos N. Pato, Edward M. Scolnick, David St Clair, Nigel M. Williams, Lyudmila Georgieva, Ivan Nikolov, N. Norton, H. Williams, Draga Toncheva, Vihra Milanova, Emma F. Thelander, Colm T. O'Dushlaine, Elaine Kenny, Emma M. Quinn, Khalid Choudhury, Susmita Datta, Jonathan Pimm, Srinivasa Thirumalai, Vinay Puri, Robert Krasucki, Jacob Lawrence, Digby Quested, Nicholas Bass, Caroline Crombie, Gillian Fraser, Soh Leh Kuan, Nicholas Walker, 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, Andrew N. Kirby, Manuel A.R. Ferreira, Mark J. Daly, Kimberly Chambert, Finny Kuruvilla, Stacey B. Gabriel, Kristin Ardlie, Jennifer L. Moran, Pamela Sklar

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Abstract

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

Original language	English (US)
Pages (from-to)	748-752
Number of pages	5
Journal	Nature
Volume	460
Issue number	7256
DOIs	https://doi.org/10.1038/nature08185
State	Published - Aug 6 2009

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Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., O'Donovan, M. C., Sullivan, P. F., Ruderfer, D. M., McQuillin, A., Morris, D. W., Oĝdushlaine, C. T., Corvin, A., Holmans, P. A., Oĝdonovan, M. C., MacGregor, S., Gurling, H., Blackwood, D. H. R., Craddock, N. J., Gill, M., Hultman, C. M., ... Sklar, P. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460(7256), 748-752. https://doi.org/10.1038/nature08185

Purcell, SM, Wray, NR, Stone, JL, Visscher, PM, O'Donovan, MC, Sullivan, PF, Ruderfer, DM, McQuillin, A, Morris, DW, Oĝdushlaine, CT, Corvin, A, Holmans, PA, Oĝdonovan, MC, MacGregor, S, Gurling, H, Blackwood, DHR, Craddock, NJ, Gill, M, Hultman, CM, Kirov, GK, Lichtenstein, P, Muir, WJ, Owen, MJ, Pato, CN, Scolnick, EM, St Clair, D, Williams, NM, Georgieva, L, Nikolov, I, Norton, N, Williams, H, Toncheva, D, Milanova, V, Thelander, EF, O'Dushlaine, CT, Kenny, E, Quinn, EM, Choudhury, K, Datta, S, Pimm, J, Thirumalai, S, Puri, V, Krasucki, R, Lawrence, J, Quested, D, Bass, N, Crombie, C, Fraser, G, Leh Kuan, S, Walker, N, 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, Kirby, AN, Ferreira, MAR, Daly, MJ, Chambert, K, Kuruvilla, F, Gabriel, SB, Ardlie, K, Moran, JL & Sklar, P 2009, 'Common polygenic variation contributes to risk of schizophrenia and bipolar disorder', Nature, vol. 460, no. 7256, pp. 748-752. https://doi.org/10.1038/nature08185

@article{b7b67e8cc9b346a9aac5baac5eec7473,

title = "Common polygenic variation contributes to risk of schizophrenia and bipolar disorder",

abstract = "Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.",

author = "Purcell, {Shaun M.} and Wray, {Naomi R.} and Stone, {Jennifer L.} and Visscher, {Peter M.} and O'Donovan, {Michael C.} and Sullivan, {Patrick F.} and Ruderfer, {Douglas M.} and Andrew McQuillin and Morris, {Derek W.} and Oĝdushlaine, {Colm T.} and Aiden Corvin and Holmans, {Peter A.} and Oĝdonovan, {Michael C.} and Stuart MacGregor and Hugh Gurling and Blackwood, {Douglas H.R.} and Craddock, {Nick J.} and Michael Gill and Hultman, {Christina M.} and Kirov, {George K.} and Paul Lichtenstein and Muir, {Walter J.} and Owen, {Michael J.} and Pato, {Carlos N.} and Scolnick, {Edward M.} and {St Clair}, David and Williams, {Nigel M.} and Lyudmila Georgieva and Ivan Nikolov and N. Norton and H. Williams and Draga Toncheva and Vihra Milanova and Thelander, {Emma F.} and O'Dushlaine, {Colm T.} and Elaine Kenny and Quinn, {Emma M.} 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 Caroline Crombie and Gillian Fraser and {Leh Kuan}, Soh and Nicholas Walker 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 Kirby, {Andrew N.} and Ferreira, {Manuel A.R.} and Daly, {Mark J.} and Kimberly Chambert and Finny Kuruvilla and Gabriel, {Stacey B.} and Kristin Ardlie and Moran, {Jennifer L.} and Pamela Sklar",

note = "Funding Information: Acknowledgements We thank the patients and families who contributed to these studies. We also thank E. Lander, N. Patterson and members of the Medical and Population Genetics group at the Broad Institute of Harvard and Massachusetts Institute of Technology for valuable discussion, and members of the Broad Biological Samples and Genetic Analysis Platforms for sample management and genotyping. We particularly thank D. Levinson and P. Gejman for allowing access to the MGS samples, and J. Shi for analytic support with the MGS samples. 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 the 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 and MH077139 (P.S.) and a Narsad Young Investigator Award (S.M.P.). The group at the Queensland Institute of Medical Research was supported by the Australian National Health and Medical Research Council (grants 389892, 442915, 496688 and 496674) and thanks S. Gordon for data preparation. 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. 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 the Wellcome Trust Clinical Research Facility (Edinburgh) and grants from The Wellcome Trust, London and the Chief Scientist Office of the Scottish Government. 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 = "2009",

month = aug,

day = "6",

doi = "10.1038/nature08185",

language = "English (US)",

volume = "460",

pages = "748--752",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7256",

}

TY - JOUR

T1 - Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

AU - Purcell, Shaun M.

AU - Wray, Naomi R.

AU - Stone, Jennifer L.

AU - Visscher, Peter M.

AU - O'Donovan, Michael C.

AU - Sullivan, Patrick F.

AU - Ruderfer, Douglas M.

AU - McQuillin, Andrew

AU - Morris, Derek W.

AU - Oĝdushlaine, Colm T.

AU - Corvin, Aiden

AU - Holmans, Peter A.

AU - Oĝdonovan, Michael C.

AU - MacGregor, Stuart

AU - Gurling, Hugh

AU - Blackwood, Douglas H.R.

AU - Craddock, Nick J.

AU - Gill, Michael

AU - Hultman, Christina M.

AU - Kirov, George K.

AU - Lichtenstein, Paul

AU - Muir, Walter J.

AU - Owen, Michael J.

AU - Pato, Carlos N.

AU - Scolnick, Edward M.

AU - St Clair, David

AU - Williams, Nigel M.

AU - Georgieva, Lyudmila

AU - Nikolov, Ivan

AU - Norton, N.

AU - Williams, H.

AU - Toncheva, Draga

AU - Milanova, Vihra

AU - Thelander, Emma F.

AU - O'Dushlaine, Colm T.

AU - Kenny, Elaine

AU - Quinn, Emma M.

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 - Crombie, Caroline

AU - Fraser, Gillian

AU - Leh Kuan, Soh

AU - Walker, Nicholas

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 - Kirby, Andrew N.

AU - Ferreira, Manuel A.R.

AU - Daly, Mark J.

AU - Chambert, Kimberly

AU - Kuruvilla, Finny

AU - Gabriel, Stacey B.

AU - Ardlie, Kristin

AU - Moran, Jennifer L.

AU - Sklar, Pamela

N1 - Funding Information: Acknowledgements We thank the patients and families who contributed to these studies. We also thank E. Lander, N. Patterson and members of the Medical and Population Genetics group at the Broad Institute of Harvard and Massachusetts Institute of Technology for valuable discussion, and members of the Broad Biological Samples and Genetic Analysis Platforms for sample management and genotyping. We particularly thank D. Levinson and P. Gejman for allowing access to the MGS samples, and J. Shi for analytic support with the MGS samples. 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 the 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 and MH077139 (P.S.) and a Narsad Young Investigator Award (S.M.P.). The group at the Queensland Institute of Medical Research was supported by the Australian National Health and Medical Research Council (grants 389892, 442915, 496688 and 496674) and thanks S. Gordon for data preparation. 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. 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 the Wellcome Trust Clinical Research Facility (Edinburgh) and grants from The Wellcome Trust, London and the Chief Scientist Office of the Scottish Government. 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 - 2009/8/6

Y1 - 2009/8/6

N2 - Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

AB - Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%. We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

UR - http://www.scopus.com/inward/record.url?scp=68449086236&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=68449086236&partnerID=8YFLogxK

U2 - 10.1038/nature08185

DO - 10.1038/nature08185

M3 - Article

C2 - 19571811

AN - SCOPUS:68449086236

SN - 0028-0836

VL - 460

SP - 748

EP - 752

JO - Nature

JF - Nature

IS - 7256

ER -

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

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