Article | Published:

Biological insights from 108 schizophrenia-associated genetic loci

Nature volume 511, pages 421427 (24 July 2014) | Download Citation

Abstract

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

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Acknowledgements

Core funding for the Psychiatric Genomics Consortium is from the US National Institute of Mental Health (U01 MH094421). We thank T. Lehner (NIMH). The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Details are provided in the Supplementary Notes. Membership of the Wellcome Trust Case Control Consortium and of the Psychosis Endophenotype International Consortium are provided in the Supplementary Notes.

Author information

Author notes

    • Wellcome Trust Case-Control Consortium

    A list of authors and affiliations appear in the Supplementary Information.

Affiliations

  1. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Stephan Ripke
    • , Benjamin M. Neale
    • , Kai-How Farh
    • , Phil Lee
    • , Brendan Bulik-Sullivan
    • , Hailiang Huang
    • , Menachem Fromer
    • , Jacqueline I. Goldstein
    •  & Mark J. Daly
  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Stephan Ripke
    • , Benjamin M. Neale
    • , Phil Lee
    • , Brendan Bulik-Sullivan
    • , Richard A. Belliveau Jr
    • , Sarah E. Bergen
    • , Elizabeth Bevilacqua
    • , Kimberly D. Chambert
    • , Menachem Fromer
    • , Giulio Genovese
    • , Colm O’Dushlaine
    • , Edward M. Scolnick
    • , Jordan W. Smoller
    • , Steven A. McCarroll
    • , Jennifer L. Moran
    • , Aarno Palotie
    • , Tracey L. Petryshen
    •  & Mark J. Daly
  3. Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Benjamin M. Neale
    • , Hailiang Huang
    • , Tune H. Pers
    • , Jacqueline I. Goldstein
    • , Joel N. Hirschhorn
    • , Alkes Price
    • , Eli A. Stahl
    • , Tõnu Esko
    •  & Mark J. Daly
  4. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin M. Neale
    • , Phil Lee
    • , Menachem Fromer
    • , Jordan W. Smoller
    •  & Aarno Palotie
  5. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin 8, Ireland.

    • Aiden Corvin
    • , Paul Cormican
    • , Gary Donohoe
    • , Derek W. Morris
    •  & Michael Gill
  6. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK.

    • James T. R. Walters
    • , Peter A. Holmans
    • , Noa Carrera
    • , Nick Craddock
    • , Valentina Escott-Price
    • , Lyudmila Georgieva
    • , Marian L. Hamshere
    • , David Kavanagh
    • , Sophie E. Legge
    • , Andrew J. Pocklington
    • , Alexander L. Richards
    • , Douglas M. Ruderfer
    • , Nigel M. Williams
    • , George Kirov
    • , Michael J. Owen
    •  & Michael C. O’Donovan
  7. National Centre for Mental Health, Cardiff University, Cardiff CF24 4HQ, UK.

    • Peter A. Holmans
    • , Nick Craddock
    • , Michael J. Owen
    •  & Michael C. O’Donovan
  8. Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK.

    • David A. Collier
    •  & Younes Mokrab
  9. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London SE5 8AF, UK.

    • David A. Collier
  10. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, DK-2800, Denmark.

    • Tune H. Pers
  11. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Tune H. Pers
    • , Joel N. Hirschhorn
    •  & Tõnu Esko
  12. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, SE-17176 Stockholm, Sweden.

    • Ingrid Agartz
    • , Erik Söderman
    •  & Erik G. Jönsson
  13. Department of Psychiatry, Diakonhjemmet Hospital, 0319 Oslo, Norway.

    • Ingrid Agartz
  14. NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway.

    • Ingrid Agartz
    • , Srdjan Djurovic
    • , Morten Mattingsdal
    • , Ingrid Melle
    • , Ole A. Andreassen
    •  & Erik G. Jönsson
  15. Centre for Integrative Register-based Research, CIRRAU, Aarhus University, DK-8210 Aarhus, Denmark.

    • Esben Agerbo
    •  & Preben B. Mortensen
  16. National Centre for Register-based Research, Aarhus University, DK-8210 Aarhus, Denmark.

    • Esben Agerbo
    •  & Preben B. Mortensen
  17. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.

    • Esben Agerbo
    • , Ditte Demontis
    • , Thomas Hansen
    • , Manuel Mattheisen
    • , Ole Mors
    • , Line Olsen
    • , Henrik B. Rasmussen
    • , Anders D. Børglum
    • , Preben B. Mortensen
    •  & Thomas Werge
  18. State Mental Hospital, 85540 Haar, Germany.

    • Margot Albus
  19. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA.

    • Madeline Alexander
    • , Claudine Laurent
    •  & Douglas F. Levinson
  20. Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30033, USA.

    • Farooq Amin
  21. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 30322, USA.

    • Farooq Amin
  22. Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

    • Silviu A. Bacanu
    • , Tim B. Bigdeli
    • , Bradley T. Webb
    •  & Brandon K. Wormley
  23. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen 37075, Germany.

    • Martin Begemann
    • , Christian Hammer
    • , Sergi Papiol
    •  & Hannelore Ehrenreich
  24. Department of Medical Genetics, University of Pécs, Pécs H-7624, Hungary.

    • Judit Bene
    •  & Bela Melegh
  25. Szentagothai Research Center, University of Pécs, Pécs H-7624, Hungary.

    • Judit Bene
    •  & Bela Melegh
  26. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden.

    • Sarah E. Bergen
    • , Anna K. Kähler
    • , Patrik K. E. Magnusson
    • , Christina M. Hultman
    •  & Patrick F. Sullivan
  27. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.

    • Donald W. Black
  28. University Medical Center Groningen, Department of Psychiatry, University of Groningen NL-9700 RB, The Netherlands.

    • Richard Bruggeman
  29. School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.

    • Nancy G. Buccola
  30. Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA.

    • Randy L. Buckner
    •  & Joshua L. Roffman
  31. Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.

    • Randy L. Buckner
  32. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Randy L. Buckner
    •  & Joshua L. Roffman
  33. Department of Psychiatry, University of California at San Francisco, San Francisco, California 94143, USA.

    • William Byerley
  34. University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, 3584 Utrecht, The Netherlands.

    • Wiepke Cahn
    • , René S. Kahn
    • , Eric Strengman
    •  & Roel A. Ophoff
  35. Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Guiqing Cai
    •  & Joseph D. Buxbaum
  36. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Guiqing Cai
    • , Kenneth L. Davis
    • , Elodie Drapeau
    • , Joseph I. Friedman
    • , Vahram Haroutunian
    • , Elena Parkhomenko
    • , Abraham Reichenberg
    • , Jeremy M. Silverman
    •  & Joseph D. Buxbaum
  37. Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, 76301 Rouen, France.

    • Dominique Campion
  38. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.

    • Rita M. Cantor
    •  & Roel A. Ophoff
  39. Schizophrenia Research Institute, Sydney NSW 2010, Australia.

    • Vaughan J. Carr
    • , Stanley V. Catts
    • , Frans A. Henskens
    • , Carmel M. Loughland
    • , Patricia T. Michie
    • , Christos Pantelis
    • , Ulrich Schall
    • , Rodney J. Scott
    •  & Assen V. Jablensky
  40. School of Psychiatry, University of New South Wales, Sydney NSW 2031, Australia.

    • Vaughan J. Carr
  41. Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, St Lucia QLD 4072, Australia.

    • Stanley V. Catts
  42. Institute of Psychology, Chinese Academy of Science, Beijing 100101, China.

    • Raymond C. K. Chan
  43. Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    • Ronald Y. L. Chen
    • , Eric Y. H. Chen
    • , Miaoxin Li
    • , Hon-Cheong So
    • , Emily H. M. Wong
    •  & Pak C. Sham
  44. State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

    • Eric Y. H. Chen
    • , Miaoxin Li
    •  & Pak C. Sham
  45. Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27514, USA.

    • Wei Cheng
  46. Castle Peak Hospital, Hong Kong, China.

    • Eric F. C. Cheung
  47. Institute of Mental Health, Singapore 539747, Singapore.

    • Siow Ann Chong
    • , Jimmy Lee Chee Keong
    • , Kang Sim
    •  & Mythily Subramaniam
  48. Department of Psychiatry, Washington University, St. Louis, Missouri 63110, USA.

    • C. Robert Cloninger
    •  & Dragan M. Svrakic
  49. Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine and Institute for Intelligent Systems and Robotics, Paris 75013, France.

    • David Cohen
  50. Blue Note Biosciences, Princeton, New Jersey 08540, USA

    • Nadine Cohen
  51. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.

    • James J. Crowley
    • , Martilias S. Farrell
    • , Paola Giusti-Rodríguez
    • , Yunjung Kim
    • , Jin P. Szatkiewicz
    • , Stephanie Williams
    •  & Patrick F. Sullivan
  52. Department of Psychological Medicine, Queen Mary University of London, London E1 1BB, UK.

    • David Curtis
  53. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6JJ, UK.

    • David Curtis
    • , Jonathan Pimm
    • , Hugh Gurling
    •  & Andrew McQuillin
  54. Sheba Medical Center, Tel Hashomer 52621, Israel.

    • Michael Davidson
    •  & Mark Weiser
  55. Department of Genomics, Life and Brain Center, D-53127 Bonn, Germany.

    • Franziska Degenhardt
    • , Stefan Herms
    • , Per Hoffmann
    • , Andrea Hofman
    • , Sven Cichon
    •  & Markus M. Nöthen
  56. Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.

    • Franziska Degenhardt
    • , Stefan Herms
    • , Per Hoffmann
    • , Andrea Hofman
    • , Sven Cichon
    •  & Markus M. Nöthen
  57. Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, B-2610 Antwerp, Belgium.

    • Jurgen Del Favero
  58. Centre for Integrative Sequencing, iSEQ, Aarhus University, DK-8000 Aarhus C, Denmark.

    • Ditte Demontis
    • , Manuel Mattheisen
    • , Ole Mors
    •  & Anders D. Børglum
  59. Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark.

    • Ditte Demontis
    • , Manuel Mattheisen
    •  & Anders D. Børglum
  60. First Department of Psychiatry, University of Athens Medical School, Athens 11528, Greece.

    • Dimitris Dikeos
    •  & George N. Papadimitriou
  61. Department of Psychiatry, University College Cork, Co. Cork, Ireland.

    • Timothy Dinan
  62. Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.

    • Srdjan Djurovic
  63. Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Co. Galway, Ireland.

    • Gary Donohoe
    •  & Derek W. Morris
  64. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois 60637, USA.

    • Jubao Duan
    • , Alan R. Sanders
    •  & Pablo V. Gejman
  65. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois 60201, USA.

    • Jubao Duan
    • , Alan R. Sanders
    •  & Pablo V. Gejman
  66. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

    • Frank Dudbridge
  67. Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje 1000, Republic of Macedonia.

    • Naser Durmishi
  68. Department of Psychiatry, University of Regensburg, 93053 Regensburg, Germany.

    • Peter Eichhammer
  69. Department of General Practice, Helsinki University Central Hospital, University of Helsinki P.O. Box 20, Tukholmankatu 8 B, FI-00014, Helsinki, Finland

    • Johan Eriksson
  70. Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki 1, Haartmaninkatu 8, FI-00290, Helsinki, Finland.

    • Johan Eriksson
  71. National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland.

    • Johan Eriksson
    •  & Veikko Salomaa
  72. Translational Technologies and Bioinformatics, Pharma Research and Early Development, F. Hoffman-La Roche, CH-4070 Basel, Switzerland.

    • Laurent Essioux
  73. Department of Psychiatry, Georgetown University School of Medicine, Washington DC 20057, USA.

    • Ayman H. Fanous
  74. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.

    • Ayman H. Fanous
  75. Departmentof Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.

    • Ayman H. Fanous
  76. Mental Health Service Line, Washington VA Medical Center, Washington DC 20422, USA.

    • Ayman H. Fanous
  77. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg , D-68159 Mannheim, Germany.

    • Josef Frank
    • , Sandra Meier
    • , Thomas G. Schulze
    • , Jana Strohmaier
    • , Stephanie H. Witt
    •  & Marcella Rietschel
  78. Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.

    • Lude Franke
    •  & Juha Karjalainen
  79. Department of Psychiatry, University of Colorado Denver, Aurora, Colorado 80045, USA.

    • Robert Freedman
    •  & Ann Olincy
  80. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095, USA.

    • Nelson B. Freimer
    •  & Roel A. Ophoff
  81. Department of Psychiatry, University of Halle, 06112 Halle, Germany.

    • Marion Friedl
    • , Ina Giegling
    • , Annette M. Hartmann
    • , Bettina Konte
    •  & Dan Rujescu
  82. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, New York 10029, USA.

    • Menachem Fromer
    • , Shaun M. Purcell
    • , Panos Roussos
    • , Douglas M. Ruderfer
    • , Eli A. Stahl
    •  & Pamela Sklar
  83. Department of Psychiatry, University of Munich, 80336, Munich, Germany.

    • Ina Giegling
    •  & Dan Rujescu
  84. Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris 75013, France.

    • Stephanie Godard
  85. Mental Health Research Centre, Russian Academy of Medical Sciences, 115522 Moscow, Russia.

    • Vera Golimbet
  86. Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, New Jersey 08869, USA.

    • Srihari Gopal
    • , Dai Wang
    •  & Qingqin S. Li
  87. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, QLD 4072, Australia.

    • Jacob Gratten
    • , S. Hong Lee
    • , Naomi R. Wray
    • , Peter M. Visscher
    •  & Bryan J. Mowry
  88. Academic Medical Centre University of Amsterdam, Department of Psychiatry, 1105 AZ Amsterdam, The Netherlands.

    • Lieuwe de Haan
    •  & Carin J. Meijer
  89. Illumina, La Jolla, California, California 92122, USA.

    • Mark Hansen
  90. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, DK-4000, Denmark.

    • Thomas Hansen
    • , Line Olsen
    • , Henrik B. Rasmussen
    •  & Thomas Werge
  91. Friedman Brain Institute, Icahn School ofMedicine at Mount Sinai, New York, New York 10029, USA.

    • Vahram Haroutunian
    • , Joseph D. Buxbaum
    •  & Pamela Sklar
  92. J. J. Peters VA Medical Center, Bronx, New York, New York 10468, USA.

    • Vahram Haroutunian
  93. Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle NSW 2308, Australia.

    • Frans A. Henskens
  94. School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle NSW 2308, Australia.

    • Frans A. Henskens
  95. Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel CH-4058, Switzerland.

    • Stefan Herms
    • , Per Hoffmann
    •  & Sven Cichon
  96. Department of Genetics, Harvard Medical School, Boston, Massachusetts, Massachusetts 02115, USA.

    • Joel N. Hirschhorn
    • , Tõnu Esko
    •  & Steven A. McCarroll
  97. Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen DK-2300, Denmark.

    • Mads V. Hollegaard
    •  & David M. Hougaard
  98. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi,470-1192, Japan.

    • Masashi Ikeda
    •  & Nakao Iwata
  99. Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, 4011 Stavanger, Norway.

    • Inge Joa
  100. Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona 08035, Spain.

    • Antonio Julià
    •  & Sara Marsal
  101. Centre for Medical Research, The University of Western Australia, Perth WA6009, Australia.

    • Luba Kalaydjieva
  102. The Perkins Institute for Medical Research, The University of Western Australia, Perth WA6009, Australia.

    • Luba Kalaydjieva
    •  & Assen V. Jablensky
  103. Department of Medical Genetics, Medical University, Sofia 1431, Bulgaria.

    • Sena Karachanak-Yankova
    •  & Draga Toncheva
  104. Department of Psychology, University of Colorado Boulder, Boulder, Colorado 80309, USA.

    • Matthew C. Keller
  105. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5T 1R8, Canada.

    • James L. Kennedy
    • , Clement C. Zai
    •  & Jo Knight
  106. Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada.

    • James L. Kennedy
    • , Clement C. Zai
    •  & Jo Knight
  107. Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

    • James L. Kennedy
    •  & Jo Knight
  108. Institute of Molecular Genetics, Russian Academy of Sciences, Moscow 123182, Russia.

    • Andrey Khrunin
    • , Svetlana Limborska
    •  & Petr Slominsky
  109. Latvian Biomedical Research and Study Centre, Riga, LV-1067, Latvia.

    • Janis Klovins
    •  & Liene Nikitina-Zake
  110. Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, California 90089, USA.

    • James A. Knowles
    • , Michele T. Pato
    •  & Carlos N. Pato
  111. Faculty of Medicine, Vilnius University, LT-01513 Vilnius, Lithuania.

    • Vaidutis Kucinskas
    •  & Zita Ausrele Kucinskiene
  112. Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.

    • Hana Kuzelova-Ptackova
    •  & Milan Macek Jr
  113. Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris 75013, France.

    • Claudine Laurent
  114. Duke-NUS Graduate Medical School, Singapore 169857.

    • Jimmy Lee Chee Keong
  115. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.

    • Bernard Lerer
  116. Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China.

    • Miaoxin Li
    •  & Pak C. Sham
  117. Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China.

    • Tao Li
    •  & Qiang Wang
  118. Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.

    • Kung-Yee Liang
  119. Department of Psychiatry, Columbia University, New York, New York 10032, USA.

    • Jeffrey Lieberman
    •  & T. Scott Stroup
  120. Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle NSW 2300, Australia.

    • Carmel M. Loughland
    •  & Ulrich Schall
  121. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 70-453 Szczecin, Poland.

    • Jan Lubinski
  122. Department of Mental Health and Substance Abuse Services; National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland.

    • Jouko Lönnqvist
    •  & Jaana Suvisaari
  123. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.

    • Brion S. Maher
  124. Department of Psychiatry, University of Bonn, D-53127 Bonn, Germany.

    • Wolfgang Maier
  125. Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital de la Pitié Salpêtrière, 75013 Paris, France.

    • Jacques Mallet
  126. Department of Genomics Mathematics, University of Bonn, D-53127 Bonn, Germany.

    • Manuel Mattheisen
  127. Research Unit, Sørlandet Hospital, 4604 Kristiansand, Norway.

    • Morten Mattingsdal
  128. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Robert W. McCarley
    • , Raquelle I. Mesholam-Gately
    • , Larry J. Seidman
    •  & Tracey L. Petryshen
  129. VA Boston Health Care System, Brockton, Massachusetts 02301, USA.

    • Robert W. McCarley
  130. Department of Psychiatry, National University of Ireland Galway, Co. Galway, Ireland.

    • Colm McDonald
  131. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH16 4SB, UK.

    • Andrew M. McIntosh
  132. Division of Psychiatry, University of Edinburgh, Edinburgh EH16 4SB, UK.

    • Andrew M. McIntosh
    •  & Douglas H. R. Blackwood
  133. Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway.

    • Ingrid Melle
    •  & Ole A. Andreassen
  134. Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, Massachusetts 02114, USA.

    • Raquelle I. Mesholam-Gately
    •  & Larry J. Seidman
  135. Estonian Genome Center, University of Tartu, Tartu 50090, Estonia.

    • Andres Metspalu
    • , Lili Milani
    • , Mari Nelis
    •  & Tõnu Esko
  136. School of Psychology, University of Newcastle, Newcastle NSW 2308, Australia.

    • Patricia T. Michie
  137. First Psychiatric Clinic, Medical University, Sofia 1431, Bulgaria.

    • Vihra Milanova
  138. Department P, Aarhus University Hospital, DK-8240 Risskov, Denmark.

    • Ole Mors
    •  & Anders D. Børglum
  139. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

    • Kieran C. Murphy
  140. King’s College London, London SE5 8AF, UK.

    • Robin M. Murray
    •  & John Powell
  141. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, 6229 HX Maastricht, The Netherlands.

    • Inez Myin-Germeys
    •  & Jim Van Os
  142. Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.

    • Bertram Müller-Myhsok
  143. Max Planck Institute of Psychiatry, 80336 Munich, Germany.

    • Bertram Müller-Myhsok
  144. Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.

    • Bertram Müller-Myhsok
  145. Department of Psychiatry and Psychotherapy, Jena University Hospital, 07743 Jena, Germany.

    • Igor Nenadic
  146. Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, St Lucia QLD 4072, Australia.

    • Deborah A. Nertney
  147. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    • Gerald Nestadt
    •  & Ann E. Pulver
  148. Department of Psychiatry, Trinity College Dublin, Dublin 2, Ireland.

    • Kristin K. Nicodemus
  149. Eli Lilly and Company,Lilly Corporate Center, Indianapolis, 46285 Indiana, USA.

    • Laura Nisenbaum
  150. Department of Clinical Sciences, Psychiatry, Umeå University, SE-901 87 Umeå, Sweden.

    • Annelie Nordin
    •  & Rolf Adolfsson
  151. DETECT Early Intervention Service for Psychosis, Blackrock, Co. Dublin, Ireland.

    • Eadbhard O’Callaghan
  152. Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast BT12 6AB, UK.

    • F. Anthony O’Neill
  153. Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, California 94720, USA.

    • Sang-Yun Oh
  154. Institute of Psychiatry, King’s College London, London SE5 8AF, UK.

    • Jim Van Os
  155. Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Vic 3053, Australia.

    • Christos Pantelis
  156. Department of Psychiatry, University of Helsinki, P.O. Box 590, FI-00029 HUS, Helsinki, Finland.

    • Tiina Paunio
  157. Public Health Genomics Unit, National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland

    • Tiina Paunio
    •  & Olli Pietiläinen
  158. Medical Faculty, University of Belgrade, 11000 Belgrade, Serbia.

    • Milica Pejovic-Milovancevic
  159. Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7160, USA.

    • Diana O. Perkins
    •  & Patrick F. Sullivan
  160. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, P.O. Box 20FI-00014, Helsinki, Finland

    • Olli Pietiläinen
    •  & Aarno Palotie
  161. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Alkes Price
  162. Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, UK.

    • Digby Quested
  163. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

    • Mark A. Reimers
    •  & Aaron R. Wolen
  164. Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Panos Roussos
    •  & Pamela Sklar
  165. PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.

    • Christian R. Schubert
    •  & Jens R. Wendland
  166. Department of Psychiatry and Psychotherapy, University of Gottingen, 37073 Göttingen, Germany.

    • Thomas G. Schulze
  167. Psychiatry and Psychotherapy Clinic, University of Erlangen, 91054 Erlangen, Germany.

    • Sibylle G. Schwab
  168. Hunter New England Health Service, Newcastle NSW 2308, Australia.

    • Rodney J. Scott
  169. School of Biomedical Sciences, University of Newcastle, Newcastle NSW 2308, Australia.

    • Rodney J. Scott
  170. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Jianxin Shi
  171. University of Iceland, Landspitali, National University Hospital, 101 Reykjavik, Iceland.

    • Engilbert Sigurdsson
  172. Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), N33, 0177 Tbilisi, Georgia.

    • Teimuraz Silagadze
  173. Research and Development, Bronx Veterans Affairs Medical Center, New York, New York 10468, USA.

    • Jeremy M. Silverman
  174. Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.

    • ChrisC. A. Spencer
  175. deCODE Genetics, 101 Reykjavik, Iceland.

    • Hreinn Stefansson
    • , Stacy Steinberg
    •  & Kari Stefansson
  176. Department of Clinical Neurology, Medical University of Vienna, 1090 Wien, Austria.

    • Elisabeth Stogmann
    •  & Fritz Zimprich
  177. Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA.

    • Richard E. Straub
    •  & Daniel R. Weinberger
  178. Department of Medical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.

    • Eric Strengman
  179. Berkshire Healthcare NHS Foundation Trust, Bracknell RG12 1BQ, UK.

    • Srinivas Thirumalai
  180. Section of Psychiatry, University of Verona, 37134 Verona, Italy.

    • Sarah Tosato
  181. Department of Psychiatry, University of Oulu, P.O. Box 5000, 90014, Finland.

    • Juha Veijola
  182. University Hospital of Oulu, P.O. Box 20, 90029 OYS, Finland.

    • Juha Veijola
  183. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.

  184. Health Research Board, Dublin 2, Ireland.

    • Dermot Walsh
  185. School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth WA6009, Australia.

    • Dieter B. Wildenauer
    •  & Assen V. Jablensky
  186. Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.

    • Hualin Simon Xi
  187. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore 138672.

    • Jianjun Liu
  188. University College London, London WC1E 6BT, UK.

  189. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.

    • Joseph D. Buxbaum
  190. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, 52428 Juelich, Germany.

    • Sven Cichon
  191. Department of Genetics, The Hebrew University of Jerusalem, 91905 Jerusalem, Israel.

    • Ariel Darvasi
  192. Neuroscience Discovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, CH-4070 Basel, Switzerland.

    • Enrico Domenici
  193. Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Medical Research Foundation Building, Perth WA6000, Australia.

    • Assen V. Jablensky
  194. Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

    • Kenneth S. Kendler
    •  & Brien P. Riley
  195. The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.

    • Todd Lencz
    •  & Anil K. Malhotra
  196. The Hofstra NS-LIJ School of Medicine, Hempstead, New York 11549, USA.

    • Todd Lencz
    •  & Anil K. Malhotra
  197. The Zucker Hillside Hospital, Glen Oaks, New York 11004, USA.

    • Todd Lencz
    •  & Anil K. Malhotra
  198. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore.

    • Jianjun Liu
  199. Queensland Centre for Mental Health Research, University of Queensland, Brisbane 4076, Queensland, Australia.

    • Bryan J. Mowry
  200. Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Tracey L. Petryshen
  201. Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000, The Netherlands.

    • Danielle Posthuma
  202. Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam 1081, The Netherlands.

    • Danielle Posthuma
  203. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam 1081, The Netherlands.

    • Danielle Posthuma
  204. University of Aberdeen, Institute of Medical Sciences, Aberdeen AB25 2ZD, UK.

    • David St Clair
  205. Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.

    • Daniel R. Weinberger
  206. Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark.

    • Thomas Werge

Consortia

  1. Schizophrenia Working Group of the Psychiatric Genomics Consortium

    Psychosis Endophenotypes International Consortium

Authors

    Contributions

    The individual studies or consortia contributing to the GWAS meta-analysis were led by R.A., O.A.A., D.H.R.B., A.D.B., E. Bramon, J.D.B., A.C., D.A.C., S.C., A.D., E. Domenici, H.E., T.E., P.V.G., M.G., H.G., C.M.H., N.I., A.V.J., E.G.J., K.S.K., G.K., J. Knight, T. Lencz, D.F.L., Q.S.L., J. Liu, A.K.M., S.A.M., A. McQuillin, J.L.M., P.B.M., B.J.M., M.M.N., M.C.O’D., R.A.O., M.J.O., A. Palotie, C.N.P., T.L.P., M.R., B.P.R., D.R., P.C.S, P. Sklar. D.St.C., P.F.S., D.R.W., J.R.W., J.T.R.W. and T.W. Together with the core statistical analysis group led by M.J.D. comprising S.R., B.M.N. and P.A.H., this group comprised the management group led by M.C.O’D. who were responsible for the management of the study and the overall content of the manuscript. Additional analyses and interpretations were contributed by E.A., B.B.-S., D.K., K.-H.F., M. Fromer, H.H., P.L., P.B.M., S.M.P., T.H.P., N.R.W. and P.M.V. The phenotype supervisory group comprised A.C., A.H.F., P.V.G., K.K.K. and B.J.M. D.A.C. led the candidate selected genes subgroup comprised of M.J.D., E. Dominici, J.A.K., A.M.H., M.C.O’D, B.P.R., D.R., E.M.S. and P. Sklar. Replication results were provided by S.S., H.S. and K.S. The remaining authors contributed to the recruitment, genotyping, or data processing for the contributing components of the meta-analysis. A.C., M.J.D., B.M.N., S.R., P.F.S. and M.C.O’D. took responsibility for the primary drafting of the manuscript which was shaped by the management group. All other authors saw, had the opportunity to comment on, and approved the final draft.

    Competing interests

    CFI statement–Several of the authors are employees of the following pharmaceutical companies; Pfizer (C.R.S., J.R.W., H.S.X.), F.Hoffman-La Roche (E.D., L.E.), Eli Lilly (D.A.C., Y.M., L.N.) and Janssen (S.G., D.W., Q.S.L.; also N.C. an ex-employee). Others are employees of deCODE genetics (S.S, H.S., K.S.). None of these companies influenced the design of the study, the interpretation of the data, or the amount of data reported, or financially profit by publication of the results which are pre-competitive. The other authors declare no competing interests.

    Corresponding author

    Correspondence to Michael C. O’Donovan.

    Results can be downloaded from the Psychiatric Genomics Consortium website (http://pgc.unc.edu) and visualized using Ricopili (http://www.broadinstitute.org/mpg/ricopili). Genotype data for the samples where the ethics permit deposition are available upon application from the NIMH Genetics Repository (https://www.nimhgenetics.org).

    Extended data

    Supplementary information

    PDF files

    1. 1.

      Supplementary Information

      This file contains Supplementary Text, Supplementary Tables 1-3, Supplementary References and Supplementary Notes (including a list of consortium members and acknowledgements) – see contents page for details.

    2. 2.

      Supplementary Figure

      This file contains Supplementary Figure 1.

    Excel files

    1. 1.

      Supplementary Table 4

      Credible causal schizophrenia SNPs, coding variants, and eQTLs. Worksheet 1: Coding variants: Index SNP is the schizophrenia associated SNP defining the schizophrenia associated region. Coding variant, R2, and gene denotes a coding credible SNP and the R2 with the index SNP, and the gene containing the coding variant. CHR (chromosome), BP (base position), A1A2 (alleles 1 and 2), frequencies of allele 1 (FRQ_A1), INFO (imputation quality) and P (P-value) refer to the index SNP in the discovery GWAS. P (incl rep) refers to replication P value for index SNP. Worksheets 2 and 3: Brain and blood eQTL: Credible SNP denotes a SNP within the schizophrenia credible set (defined in supplementary material) that is also a cis eQTL (transcript within 1Mb, PeQTL<1x10-4). P(cSCZ) is the schizophrenia (discovery) GWAS association P-value for the credible SNP. The Prob(cSCZ) is the normalized probability of the credible variant being causal for schizophrenia. N(cSCZ) is the number of variants in the credible set of schizophrenia variants within a region spanned by eQTLs at P<10-4. eQTL SNP is the most significant expression associated SNP in the region for the gene in next column (N.B., many regions have an eQTL for more than 1 gene). eQTLgene is the gene that is linked to the eQTL SNP. P(eQTL) is the association P-value between the eQTL SNP and the eQTLgene in the previous two columns. Prob(eQTL) is the normalized probability that the eQTL SNP is also the causal SNP for schizophrenia (high values mean higher probability of being causal). eQTLcumsum is the cumulative sum of the probability of all SNPs into the region, up to the inclusion of the max eQTL in locus ordered by probability of being the functional SNP. PeQTL(SCZ) is the schizophrenia association P-value for the eQTL SNP. R2 (cSCZ/ eQTL) is the R2 between the credibleSNP and eQTL SNP. Associations to schizophrenia that are plausibly explained by an eQTL are in bold. Separate worksheets provide information on brain and blood eQTL analyses. Distinct loci are alternately shaded/unshaded.

    2. 2.

      Supplementary Table 5

      Pathway analyses by ALIGATOR and INRICH. Enrichment analyses using ALIGATOR and INRICH were performed as described in Supplementary Text. Pathway ID denotes the pathway source: GO (Gene ontology; http://www.geneontology.org), KEGG (Kyoto Encyclopaedia of Genes and Genomes; http://www.genome.jp/kegg), PAN-PW (PANTHER; http://www.pantherdb.org/pathway), Reactome (http://www.reactome.org/download), BioCarta (downloaded from the Molecular Signatures Database v4.0 http://www.broadinstitute.org/gsea/msigdb/index.jsp), MGI (Mouse Genome Informatics; http://www.informatics.jax.org), and NCI pathways (NCI: http://pid.nci.nih.gov).

    3. 3.

      Supplementary Table 7

      Risk Profile Score Analyses. Risk Profile Score (RPS) analysis was performed as described in supplementary text. RPS datasets tab provides the name given for sample in which RPS was performed (target label) and the datasets included (defined in Supplementary Table 1). The GWAS data used to define the risk alleles for RPS analysis represents the remaining GWAS samples. For various GWAS P-value thresholds (denoted PT), we calculated: 1) the significance of the case-control score difference was analyzed (P tab), 2) the proportion of variance explained (Nagelkerke’s R2, R2 tab), 3) the proportion of variance on the liability scale explained by RPS (h2I tab) with standard error in brackets, 4) area under the receiver operator characteristic curve (AUC tab), and 5) odds ratio for the 10th RPS decile group compared with lowest decile with confidence interval in brackets. Ncases tab denotes number of cases in each target set.

    4. 4.

      Supplementary Table 6

      RPS analysis of MGS sample. Risk Profile Score (RPS) analyses was performed using the MGS dataset as target, using three distinct published results for SCZ GWAS, from the (1) ISC (2009) study of 2615 cases and 3338 controls11 (denoted ISC columns) (2) PGC1 (excluding MGS, denoted PGC1 columns) with 9320 cases and 10228 controls22, (3) current meta analysis (excluding MGS, denoted Current columns) with 32838 cases and 44357 controls. For various GWAS P value thresholds (denoted PT), we calculated 1) the significance of the case-control score difference was analyzed (P tab) 2) The proportion of variance explained (Nagelkerke’s R2, R2 tab) 3) The proportion of variance on the liability scale explained by RPS (h2I tab) with standard error in brackets 4) Area under the receiver operator characteristic curve (AUC tab) and 5) Odds ratio for 10th RPS decile group compared with lowest decile with confidence interval in brackets. Ncases tab denotes number of cases in each target set.

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    DOI

    https://doi.org/10.1038/nature13595

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