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Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Nature Genetics volume 45, pages 11501159 (2013) | Download Citation

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Abstract

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300–10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

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Acknowledgements

We are deeply grateful for the participation of all subjects contributing to this research and to the collection team that worked to recruit them: E. Flordal-Thelander, A.-B. Holmgren, M. Hallin, M. Lundin, A.-K. Sundberg, C. Pettersson, R. Satgunanthan-Dawoud, S. Hassellund, M. Rådstrom, B. Ohlander, L. Nyrén and I. Kizling. Funding support was provided by the NIMH (R01 MH077139 to P.F.S. and R01 MH095034 to P.S.), the Stanley Center for Psychiatric Research, the Sylvan Herman Foundation, the Friedman Brain Institute at the Mount Sinai School of Medicine, the Karolinska Institutet, Karolinska University Hospital, the Swedish Research Council, the Swedish County Council, the Söderström Königska Foundation and the Netherlands Scientific Organization (NWO 645-000-003). SGENE was supported by European Union grant HEALTH-F2-2009-223423 (project PsychCNVs). The study of the Aarhus sample was supported by grants from the Danish Strategic Research Council, H. Lundbeck A/S, the Faculty of Health Sciences at Aarhus University, the Lundbeck Foundation and the Stanley Research Foundation. The Wellcome Trust Case Control Consortium 2 project collection was funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z). The funders had no role in study design, execution or analysis or in manuscript preparation.

Author information

Author notes

    • Stephan Ripke
    •  & Colm O'Dushlaine

    These authors contributed equally to this work.

    • Christina M Hultman
    •  & Patrick F Sullivan

    These authors jointly directed this work.

Affiliations

  1. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Stephan Ripke
    • , Menachem Fromer
    • , Brendan K Bulik-Sullivan
    • , Benjamin M Neale
    •  & Shaun Purcell
  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Stephan Ripke
    • , Colm O'Dushlaine
    • , Kimberly Chambert
    • , Jennifer L Moran
    • , Menachem Fromer
    • , Nick Sanchez
    • , Benjamin M Neale
    • , Edward Scolnick
    • , Shaun Purcell
    •  & Steven A McCarroll
  3. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Anna K Kähler
    • , Ann L Collins
    • , James J Crowley
    • , Yunjung Kim
    • , Stephanie Williams
    •  & Patrick F Sullivan
  4. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Anna K Kähler
    • , Susanne Akterin
    • , Sarah E Bergen
    • , Patrik K E Magnusson
    • , Christina M Hultman
    •  & Patrick F Sullivan
  5. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

    • Anna K Kähler
  6. Department of Psychiatry, Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Menachem Fromer
    • , Eli A Stahl
    • , Douglas Ruderfer
    • , Jeremy M Silverman
    • , Shaun Purcell
    •  & Pamela Sklar
  7. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.

    • Sang Hong Lee
    • , Naomi R Wray
    • , Bryan J Mowry
    •  & Deborah A Nertney
  8. Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Kai Xia
    •  & Patrick F Sullivan
  9. deCODE Genetics, Reykjavik, Iceland.

    • Francesco Bettella
    • , Hreinn Stefansson
    • , Stacy Steinberg
    •  & Kari Stefansson
  10. Aarhus University Hospital, Risskov, Denmark.

    • Anders D Borglum
  11. Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark.

    • Anders D Borglum
  12. Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus and Copenhagen, Denmark.

    • Anders D Borglum
    • , Ole Mors
    •  & Preben B Mortensen
  13. Department of Psychiatry, Trinity College Dublin, Dublin, Ireland.

    • Paul Cormican
    • , Michael Gill
    • , Derek W Morris
    •  & Aiden P Corvin
  14. Medical Research Council (MRC) Centre for Psychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, UK.

    • Nick Craddock
    • , Marian L Hamshere
    • , Peter Holmans
    • , Michael J Owen
    • , Alexander L Richards
    • , James T Walters
    • , Michael C O'Donovan
    • , Nadine Norton
    •  & Nigel M Williams
  15. Department of Functional Genomics, Clinical Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam and VU Medical Center, Amsterdam, The Netherlands.

    • Christiaan de Leeuw
    • , Danielle Posthuma
    •  & Matthijs Verhage
  16. Institute for Computing and Information Sciences, Radboud University, Nijmegen, The Netherlands.

    • Christiaan de Leeuw
  17. University Clinic of Psychiatry, Department of Child and Adolescent Psychiatry, Skopje, Republic of Macedonia.

    • Naser Durmishi
  18. Neuropsychiatric Genetics Research Group, Trinity College Dublin, Dublin, Ireland.

    • Michael Gill
    • , Derek W Morris
    •  & Aiden P Corvin
  19. Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia.

    • Vera Golimbet
  20. Statens Serum Institut, Copenhagen, Denmark.

    • David M Hougaard
  21. Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Kenneth S Kendler
    •  & Brien P Riley
  22. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Kenneth S Kendler
    • , Brien P Riley
    • , Robert Ribble
    •  & Brandon Wormley
  23. Institute of Psychiatry at King's College London, London, UK.

    • Kuang Lin
    • , John Powell
    • , Maria J Arranz
    • , Elvira Bramon
    • , David Collier
    • , Conrad Iyegbe
    • , Cathryn M Lewis
    • , Robin M Murray
    • , Jim Van Os
    •  & Muriel Walshe
  24. Centre for Psychiatric Research, Aarhus University Hospital, Risskov, Denmark.

    • Ole Mors
  25. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.

    • Preben B Mortensen
  26. Centre for Public Health, Queen's University, Belfast, UK.

    • Francis A O'Neill
  27. University of Belgrade, Faculty of Medicine, Belgrade, Serbia.

    • Milica Pejovic Milovancevic
  28. Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands.

    • Danielle Posthuma
  29. Department of Neuroscience, King's College London, London, UK.

    • John Powell
  30. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.

    • Brien P Riley
  31. Department of Psychiatry, University of Halle, Halle, Germany.

    • Dan Rujescu
  32. Department of Psychiatry, University of Munich, Munich, Germany.

    • Dan Rujescu
  33. Department of Psychiatry, University of Iceland, Reykjavik, Iceland.

    • Engilbert Sigurdsson
  34. Department of Psychiatry, Tbilisi State Medical University, Tbilisi, Georgia.

    • Teimuraz Silagadze
  35. Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam, The Netherlands.

    • August B Smit
  36. Department of Molecular and Cellular Neuroscience, VU University Amsterdam, Amsterdam, The Netherlands.

    • August B Smit
  37. Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaana Suvisaari
  38. Section of Psychiatry, University of Verona, Verona, Italy.

    • Sarah Tosato
  39. Institute of Cognitive Neuroscience, University College London, London, UK.

    • Elvira Bramon
  40. Mental Health Sciences Unit, University College London, London, UK.

    • Elvira Bramon
  41. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Shaun Purcell
  42. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Steven A McCarroll
  43. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA.

    • Douglas F Levinson
    •  & Madeline Alexander
  44. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem and University of Chicago, Evanston, Illinois, USA.

    • Pablo V Gejman
    • , Jubao Duan
    •  & Alan R Sanders
  45. Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Brain and Spinal Cord Institute, Paris, France.

    • Claudine Laurent
  46. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Ann E Pulver
    •  & Gerald Nestadt
  47. Psychiatry and Psychotherapy Clinic, Friedrich-Alexander University, Erlangen-Nuremberg, Erlangen, Germany.

    • Sibylle G Schwab
  48. Department of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Western Australia, Australia.

    • Dieter B Wildenauer
  49. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

    • Frank Dudbridge
  50. Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Jianxin Shi
  51. State Mental Hospital, Haar, Germany.

    • Margot Albus
  52. INSERM U1079, Faculté de Médecine, Rouen, France.

    • Dominique Campion
  53. Pierre and Marie Curie Faculty of Medicine, Institute for Intelligent Systems and Robotics, Paris, France.

    • David Cohen
  54. First Department of Psychiatry, University of Athens Medical School, Athens, Greece.

    • Dimitris Dikeos
    •  & George N Papadimitriou
  55. Department of Psychiatry, University of Regensburg, Regensburg, Germany.

    • Peter Eichhammer
  56. INSERM, Institut de Myologie, Hôpital Pitié Salpêtrière, Paris, France.

    • Stephanie Godard
  57. Illumina, Inc., La Jolla, California, USA.

    • Mark Hansen
  58. Department of Psychiatry, Hadassah–Hebrew University Medical Center, Jerusalem, Israel.

    • F Bernard Lerer
  59. Department of Biostatistics, Johns Hopkins University, Baltimore, Maryland, USA.

    • Kung-Yee Liang
  60. Department of Psychiatry, University of Bonn, Bonn, Germany.

    • Wolfgang Maier
  61. CNRS, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital Pitié Salpêtrière, Paris, France.

    • Jacques Mallet
  62. The Health Research Board, Dublin, Ireland.

    • Dermot Walsh
  63. Fundacio de Docencia i Recerca Mutua de Terrassa, Universitat de Barcelona, Barcelona, Spain.

    • Maria J Arranz
  64. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Steven Bakker
    •  & Rene S Kahn
  65. Child and Adolescent Psychiatry, University of Technology Dresden, Dresden, Germany.

    • Stephan Bender
  66. Section for Experimental Psychopathology, General Psychiatry, Heidelberg, Germany.

    • Stephan Bender
    •  & Matthias Weisbrod
  67. Discovery Neuroscience Research, Eli Lilly and Company, London, UK.

    • David Collier
  68. CIBERSAM (Centro Investigación Biomédica en Red Salud Mental), Madrid, Spain.

    • Benedicto Crespo-Facorro
    •  & Ignacio Mata
  69. University Hospital Marques de Valdecilla, Instituto de Formacion e Investigacion Marques de Valdecilla, University of Cantabria, Santander, Spain.

    • Benedicto Crespo-Facorro
    •  & Ignacio Mata
  70. Division of Psychiatry, University of Edinburgh, Edinburgh, UK.

    • Jeremy Hall
    • , Stephen Lawrie
    •  & Andrew McIntosh
  71. Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, Western Australia, Australia.

    • Assen Jablensky
  72. Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.

    • Luba Kalaydjieva
  73. Western Australian Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia.

    • Luba Kalaydjieva
  74. Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

    • Don H Linszen
  75. Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, California, USA.

    • Roel A Ophoff
  76. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, The Netherlands.

    • Jim Van Os
  77. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

    • Durk Wiersma
  78. Department of Statistics, University of Oxford, Oxford, UK.

    • Peter Donnelly
  79. Wellcome Trust Centre for Human Genetics, Oxford, UK.

    • Peter Donnelly
    • , Anna Rautanen
    • , Chris C A Spencer
    • , Gavin Band
    • , Céline Bellenguez
    • , Colin Freeman
    • , Garrett Hellenthal
    • , Eleni Giannoulatou
    • , Matti Pirinen
    • , Richard D Pearson
    • , Amy Strange
    • , Zhan Su
    •  & Damjan Vukcevic
  80. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Ines Barroso
    • , Panos Deloukas
    • , Cordelia Langford
    • , Sarah E Hunt
    • , Sarah Edkins
    • , Rhian Gwilliam
    • , Hannah Blackburn
    • , Suzannah J Bumpstead
    • , Serge Dronov
    • , Matthew Gillman
    • , Emma Gray
    • , Naomi Hammond
    • , Alagurevathi Jayakumar
    • , Owen T McCann
    • , Jennifer Liddle
    • , Simon C Potter
    • , Radhi Ravindrarajah
    • , Michelle Ricketts
    • , Avazeh Tashakkori-Ghanbaria
    • , Matthew J Waller
    • , Paul Weston
    • , Sara Widaa
    •  & Pamela Whittaker
  81. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK.

    • Jenefer M Blackwell
  82. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Subiaco, Western Australia, Australia.

    • Jenefer M Blackwell
  83. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.

    • Matthew A Brown
  84. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  85. Department of Epidemiology and Public Health, University College London, London, UK.

    • Juan P Casas
  86. Molecular and Physiological Sciences, The Wellcome Trust, London, UK.

    • Audrey Duncanson
  87. Peninsula School of Medicine and Dentistry, Plymouth University, Plymouth, UK.

    • Janusz Jankowski
  88. Clinical Neurosciences, St. George's University of London, London, UK.

    • Hugh S Markus
  89. Department of Medical and Molecular Genetics, School of Medicine, King's College London, Guy's Hospital, London, UK.

    • Christopher G Mathew
    •  & Richard C Trembath
  90. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  91. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

    • Robert Plomin
  92. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
  93. Institute of Ophthalmology, University College London, London, UK.

    • Ananth C Viswanathan
  94. National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust, London, UK.

    • Ananth C Viswanathan
  95. Department of Molecular Neuroscience, Institute of Neurology, London, UK.

    • Nicholas W Wood
  96. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy

Consortia

  1. Multicenter Genetic Studies of Schizophrenia Consortium

  2. Psychosis Endophenotypes International Consortium

  3. Wellcome Trust Case Control Consortium 2

    Management Committee:

    Data and Analysis Group:

    DNA, Genotyping, Data QC and Informatics Group:

    Publications Committee:

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Contributions

S.R., C.O., E.A.S., M.F., N.R.W., N.S., S.E.B., S.H.L., A.B.S., A.L.R., B.K.B.-S., B.M.N., C.d.L., D.P., D. Ruderfer, F.B., J.P., K.L., M.L.H., M.V., P.H., S.S., S.A.M., S.P. and P.F.S. conducted statistical analyses. A.D.B., D.M.H., D. Rujescu, E. Sigurdsson, J.S., M.P.M., N.D., O.M., P.B.M., S.T., T.S. and V.G. ascertained subjects. A.L.C., J.J.C., S.W., Y.K., K.X. and P.F.S. performed bioinformatics analyses. K.C., J.L.M. and S.A. managed the project. B.P.R., D.W.M., F.A.O., H.S., J.T.W., K.S.K., M.G., M.J.O., N.C., P.C., the Multicenter Genetic Studies of Schizophrenia, the Psychosis Endophenotypes International Consortium, the Wellcome Trust Case Control Consortium 2, A.P.C., E.B., K.S. and M.C.O. provided replication samples and genotypes. A.K.K. interfaced with Swedish national registers. The manuscript was written by P.K.E.M., S.A.M., S.P., P.S., C.M.H. and P.F.S. The study was designed by S.P., P.S., C.M.H. and P.F.S. Funding was obtained by E. Scolnick, P.S., C.M.H. and P.F.S.

Competing interests

P.F.S. was on the scientific advisory board of Expression Analysis (Durham, North Carolina, USA). P.S. is on the Board of Directors of Catalytic, Inc. The other authors report no conflicts.

Corresponding author

Correspondence to Patrick F Sullivan.

Supplementary information

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    Supplementary Figures and Text

    Supplementary Figures 1–13 and Supplementary Table 1–9 and Supplementary Note

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.2742

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