Biological insights from 108 schizophrenia-associated genetic loci (original) (raw)

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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

  1. Wellcome Trust Case-Control Consortium and Thomas Werge: A list of authors and affiliations appear in the Supplementary Information.
  2. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
  3. University College London, London WC1E 6BT, UK.

Authors and Affiliations

  1. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, 02114, Massachusetts, 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, 02142, Massachusetts, 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, 02142, Massachusetts, 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, 02114, Massachusetts, USA
    Benjamin M. Neale, Phil Lee, Menachem Fromer, Jordan W. Smoller & Aarno Palotie
  5. Department of Psychiatry, Neuropsychiatric Genetics Research Group, 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. Department of Systems Biology, Center for Biological Sequence Analysis, 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, 02115, Massachusetts, 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, 94305, California, 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, 30322, Georgia, USA
    Farooq Amin
  22. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298, Virginia, 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, 52242, Iowa, USA
    Donald W. Black
  28. Department of Psychiatry, University Medical Center Groningen, University of Groningen NL-9700 RB, The Netherlands
    Richard Bruggeman
  29. School of Nursing, Louisiana State University Health Sciences Center, New Orleans, 70112, Louisiana, USA
    Nancy G. Buccola
  30. Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, 02129, Massachusetts, USA
    Randy L. Buckner & Joshua L. Roffman
  31. Center for Brain Science, Harvard University, Cambridge, 02138, Massachusetts, USA
    Randy L. Buckner
  32. Department of Psychiatry, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
    Randy L. Buckner & Joshua L. Roffman
  33. Department of Psychiatry, University of California at San Francisco, San Francisco, 94143, California, USA
    William Byerley
  34. Department of Psychiatry, University Medical Center Utrecht, 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, 10029, New York, USA
    Guiqing Cai & Joseph D. Buxbaum
  36. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, 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, 90095, California, 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, 27514, North Carolina, 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, 63110, Missouri, 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, 08540, New Jersey, USA
    Nadine Cohen
  51. Department of Genetics, University of North Carolina, Chapel Hill, 27599-7264, North Carolina, 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. Division of Psychiatry, Molecular Psychiatry Laboratory, 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. VIB Department of Molecular Genetics, Applied Molecular Genomics Unit, 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, 60637, Illinois, USA
    Jubao Duan, Alan R. Sanders & Pablo V. Gejman
  65. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, 60201, Illinois, 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, 20057, Washington DC, 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, 23298, Virginia, USA
    Ayman H. Fanous
  76. Mental Health Service Line, Washington VA Medical Center, 20422, Washington DC, 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, 80045, Colorado, USA
    Robert Freedman & Ann Olincy
  80. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, 90095, California, 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, 10029, New York, 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, 08869, New Jersey, 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. Department of Psychiatry, Academic Medical Centre University of Amsterdam, 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, 10029, New York, USA
    Vahram Haroutunian, Joseph D. Buxbaum & Pamela Sklar
  92. J. J. Peters VA Medical Center, Bronx, New York, 10468, New York, 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. Department of Clinical Biochemistry, Section of Neonatal Screening and Hormones, 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. Department of Psychiatry, Regional Centre for Clinical Research in Psychosis, 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, 80309, Colorado, 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, 90089, California, 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, 21205, Maryland, USA
    Kung-Yee Liang
  119. Department of Psychiatry, Columbia University, New York, 10032, New York, 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. National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland.,
    Jouko Lönnqvist & Jaana Suvisaari
  124. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, 21205, Maryland, USA
    Brion S. Maher
  125. Department of Psychiatry, University of Bonn, D-53127 Bonn, Germany.,
    Wolfgang Maier
  126. 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
  127. Department of Genomics Mathematics, University of Bonn, D-53127 Bonn, Germany.,
    Manuel Mattheisen
  128. Research Unit, Sørlandet Hospital, 4604 Kristiansand, Norway.,
    Morten Mattingsdal
  129. Department of Psychiatry, Harvard Medical School, Boston, 02115, Massachusetts, USA
    Robert W. McCarley, Raquelle I. Mesholam-Gately, Larry J. Seidman & Tracey L. Petryshen
  130. VA Boston Health Care System, Brockton, 02301, Massachusetts, USA
    Robert W. McCarley
  131. Department of Psychiatry, National University of Ireland Galway, Co. Galway, Ireland
    Colm McDonald
  132. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH16 4SB, UK.,
    Andrew M. McIntosh
  133. Division of Psychiatry, University of Edinburgh, Edinburgh EH16 4SB, UK.,
    Andrew M. McIntosh & Douglas H. R. Blackwood
  134. Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway.,
    Ingrid Melle & Ole A. Andreassen
  135. Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, 02114, Massachusetts, USA
    Raquelle I. Mesholam-Gately & Larry J. Seidman
  136. Estonian Genome Center, University of Tartu, Tartu 50090, Estonia.,
    Andres Metspalu, Lili Milani, Mari Nelis & Tõnu Esko
  137. School of Psychology, University of Newcastle, Newcastle NSW 2308, Australia.,
    Patricia T. Michie
  138. First Psychiatric Clinic, Medical University, Sofia 1431, Bulgaria.,
    Vihra Milanova
  139. Department P, Aarhus University Hospital, DK-8240 Risskov, Denmark.,
    Ole Mors & Anders D. Børglum
  140. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 2, Ireland.,
    Kieran C. Murphy
  141. King’s College London, London SE5 8AF, UK.,
    Robin M. Murray & John Powell
  142. Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, 6229 HX Maastricht, The Netherlands.,
    Inez Myin-Germeys & Jim Van Os
  143. Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.,
    Bertram Müller-Myhsok
  144. Max Planck Institute of Psychiatry, 80336 Munich, Germany.,
    Bertram Müller-Myhsok
  145. Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.,
    Bertram Müller-Myhsok
  146. Department of Psychiatry and Psychotherapy, Jena University Hospital, 07743 Jena, Germany.,
    Igor Nenadic
  147. 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
  148. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA
    Gerald Nestadt & Ann E. Pulver
  149. Department of Psychiatry, Trinity College Dublin, Dublin 2, Ireland.,
    Kristin K. Nicodemus
  150. Eli Lilly and Company,Lilly Corporate Center, Indianapolis, 46285, Indiana, USA
    Laura Nisenbaum
  151. Department of Clinical Sciences, Psychiatry, Umeå University, SE-901 87 Umeå, Sweden.,
    Annelie Nordin & Rolf Adolfsson
  152. DETECT Early Intervention Service for Psychosis, Blackrock, Co. Dublin, Ireland.,
    Eadbhard O’Callaghan
  153. Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast BT12 6AB, UK.,
    F. Anthony O’Neill
  154. Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, 94720, California, USA
    Sang-Yun Oh
  155. Institute of Psychiatry, King’s College London, London SE5 8AF, UK.,
    Jim Van Os
  156. Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Vic 3053, Australia.,
    Christos Pantelis
  157. Department of Psychiatry, University of Helsinki, P.O. Box 590, FI-00029 HUS, Helsinki, Finland.,
    Tiina Paunio
  158. Public Health Genomics Unit, National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland,
    Tiina Paunio & Olli Pietiläinen
  159. Medical Faculty, University of Belgrade, 11000 Belgrade, Serbia.,
    Milica Pejovic-Milovancevic
  160. Department of Psychiatry, University of North Carolina, Chapel Hill, 27599-7160, North Carolina, USA
    Diana O. Perkins & Patrick F. Sullivan
  161. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, P.O. Box 20FI-00014, Helsinki, Finland,
    Olli Pietiläinen & Aarno Palotie
  162. Department of Epidemiology, Harvard School of Public Health, Boston, 02115, Massachusetts, USA
    Alkes Price
  163. Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, UK.,
    Digby Quested
  164. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298, Virginia, USA
    Mark A. Reimers & Aaron R. Wolen
  165. Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA
    Panos Roussos & Pamela Sklar
  166. PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, 02139, Massachusetts, USA
    Christian R. Schubert & Jens R. Wendland
  167. Department of Psychiatry and Psychotherapy, University of Gottingen, 37073 Göttingen, Germany.,
    Thomas G. Schulze
  168. Psychiatry and Psychotherapy Clinic, University of Erlangen, 91054 Erlangen, Germany.,
    Sibylle G. Schwab
  169. Hunter New England Health Service, Newcastle NSW 2308, Australia.,
    Rodney J. Scott
  170. School of Biomedical Sciences, University of Newcastle, Newcastle NSW 2308, Australia.,
    Rodney J. Scott
  171. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, Maryland, USA
    Jianxin Shi
  172. University of Iceland, Landspitali, National University Hospital, 101 Reykjavik, Iceland.,
    Engilbert Sigurdsson
  173. Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), N33, 0177 Tbilisi, Georgia.,
    Teimuraz Silagadze
  174. Research and Development, Bronx Veterans Affairs Medical Center, New York, 10468, New York, USA
    Jeremy M. Silverman
  175. Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.,
    ChrisC. A. Spencer
  176. deCODE Genetics, 101 Reykjavik, Iceland.,
    Hreinn Stefansson, Stacy Steinberg & Kari Stefansson
  177. Department of Clinical Neurology, Medical University of Vienna, 1090 Wien, Austria.,
    Elisabeth Stogmann & Fritz Zimprich
  178. Lieber Institute for Brain Development, Baltimore, 21205, Maryland, USA
    Richard E. Straub & Daniel R. Weinberger
  179. Department of Medical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.,
    Eric Strengman
  180. Berkshire Healthcare NHS Foundation Trust, Bracknell RG12 1BQ, UK.,
    Srinivas Thirumalai
  181. Section of Psychiatry, University of Verona, 37134 Verona, Italy.,
    Sarah Tosato
  182. Department of Psychiatry, University of Oulu, P.O. Box 5000, 90014, Finland.,
    Juha Veijola
  183. University Hospital of Oulu, P.O. Box 20, 90029 OYS, Finland.,
    Juha Veijola
  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, 02139, Massachusetts, USA
    Hualin Simon Xi
  187. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore 138672.,
    Jianjun Liu
  188. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA
    Joseph D. Buxbaum
  189. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, 52428 Juelich, Germany.,
    Sven Cichon
  190. Department of Genetics, The Hebrew University of Jerusalem, 91905 Jerusalem, Israel.,
    Ariel Darvasi
  191. Neuroscience Discovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, CH-4070 Basel, Switzerland.,
    Enrico Domenici
  192. 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
  193. Departments of Psychiatry and Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, 23298, Virginia, USA
    Kenneth S. Kendler & Brien P. Riley
  194. The Feinstein Institute for Medical Research, Manhasset, 11030, New York, USA
    Todd Lencz & Anil K. Malhotra
  195. The Hofstra NS-LIJ School of Medicine, Hempstead, 11549, New York, USA
    Todd Lencz & Anil K. Malhotra
  196. The Zucker Hillside Hospital, Glen Oaks, 11004, New York, USA
    Todd Lencz & Anil K. Malhotra
  197. Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore.,
    Jianjun Liu
  198. Queensland Centre for Mental Health Research, University of Queensland, Brisbane 4076, Queensland, Australia.,
    Bryan J. Mowry
  199. Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
    Tracey L. Petryshen
  200. Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000, The Netherlands.,
    Danielle Posthuma
  201. Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam 1081, The Netherlands.,
    Danielle Posthuma
  202. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam 1081, The Netherlands.,
    Danielle Posthuma
  203. University of Aberdeen, Institute of Medical Sciences, Aberdeen AB25 2ZD, UK.,
    David St Clair
  204. Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, 21205, Maryland, USA
    Daniel R. Weinberger
  205. Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark.,
    Thomas Werge

Consortia

Schizophrenia Working Group of the Psychiatric Genomics Consortium

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.

Corresponding author

Correspondence toMichael C. O’Donovan.

Ethics declarations

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.

Additional information

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).

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

Extended data figures and tables

Extended Data Figure 1 Homogeneity of effects across studies.

Plot of the first two principal components (PCs) from principal components analysis (PCA) of the logistic regression β coefficients for autosomal genome-wide significant associations. The input data were the β coefficients from 52 samples for 112 independent SNP associations (excluding 3 chrX SNPs and 13 SNPs with missing values in Asian samples). PCAs were weighted by the number of cases. Each circle shows the location of a study on PC1 and PC2. Circle size and colour are proportional to the number of cases in each sample (larger and darker red circles correspond to more cases). Most samples cluster. Outliers had either small numbers of cases (‘small’) or were genotyped on older arrays. Abbreviations: a500 (Affymetrix 500K); a5 (Affymetrix 5.0). Studies that did not use conventional research interviews are in the central cluster (CLOZUK, Sweden, and Denmark-Aarhus studies, see Supplementary Methods for sample descriptions).

Extended Data Figure 2 Quantile-quantile plot.

Quantile-quantile plot of the discovery genome-wide association meta-analysis of 49 case control samples (34,241 cases and 45,604 controls) and 3 family based association studies (1,235 parent affected-offspring trios). Expected –log10 P values are those expected under the null hypothesis. Observed are the GWAS association results derived by logistic regression (2-tailed) as in Fig. 1. For clarity, we avoided expansion of the y axis by setting the smallest association P values to 10−12. The shaded area surrounded by a red line indicates the 95% confidence interval under the null. λGC is the observed median χ2 test statistic divided by the median expected χ2 test statistic under the null hypothesis.

Extended Data Figure 3 Linkage disequilibrium score regression consistent with polygenic inheritance.

The relationship between marker χ_2_ association statistics and linkage disequilibrium (LD) as measured by the linkage disequilibrium score. Linkage disequilibrium score is the sum of the r_2 values between a variant and all other known variants within a 1 cM window, and quantifies the amount of genetic variation tagged by that variant. Variants were grouped into 50 equal-sized bins based on linkage disequilibrium score rank. Linkage disequilibrium score bin and mean χ_2 denotes mean linkage disequilibrium score and test statistic for markers each bin. a, b, We simulated (Supplementary Methods) test statistics under two scenarios: a, no true association, inflation due to population stratification; and b, polygenic inheritance (λ = 1.32), in which we assigned independent and identically distributed per-normalized-genotype effects to a randomly selected subset of variants. c, Results from the PGC schizophrenia GWAS (λ = 1.48). The real data are strikingly similar to the simulated data summarized in b but not a. The intercept estimates the inflation in the mean χ_2_ that results from confounding biases, such as cryptic relatedness or population stratification. Thus, the intercept of 1.066 for the schizophrenia GWAS suggests that ∼90% of the inflation in the mean χ_2_ results from polygenic signal. The results of the simulations are also consistent with theoretical expectation (see Supplementary Methods). λ is the median χ2 test statistic from the simulations (a, b) or the observed data (c) divided by the median expected χ2 test statistic under the null hypothesis.

Extended Data Figure 4 Enrichment of associations in tissues and cells.

Genes whose transcriptional start is nearest to the most associated SNP at each schizophrenia-associated locus were tested for enriched expression in purified brain cell subsets obtained from mouse ribotagged lines41 using enrichment analysis described in the Supplementary Methods. The red dotted line indicates P = 0.05.

Extended Data Figure 5 MGS risk profile score analysis.

Polygenic risk profile score (RPS) analyses using the MGS18 sample as target, and deriving risk alleles from three published schizophrenia data sets (x axis): ISC (2,615 cases and 3,338 controls)10, PGC1 (excluding MGS, 9,320 cases and 10,228 controls)16, and the current meta-analysis (excluding MGS) with 32,838 cases and 44,357 controls. Samples sizes differ slightly from the original publications due to different analytical procedures. This shows the increasing RPS prediction with increasing training data set size reflecting improved precision of estimates of the SNP effect sizes. The proportion of variance explained (y axis; Nagelkerke’s _R_2) was computed by comparison of a full model (covariates + RPS) score to a reduced model (covariates only). Ten different P value thresholds (_P_T) for selecting risk alleles are denoted by the colour of each bar (legend above plot). For significance testing, see the bottom legend which denotes the P value for the test that _R_2 is different from zero. All numerical data and methods used to generate these plots are available in Supplementary Table 6 and Supplementary Methods.

Extended Data Figure 6 Risk profile score analysis.

We defined 40 target subgroups of the primary GWAS data set and performed 40 leave-one-out GWAS analyses (see Supplementary Methods and Supplementary Table 7) from which we derived risk alleles for RPS analysis (x axis) for each target subgroup. a, The proportion of variance explained (y axis; Nagelkerke’s _R_2) was computed for each target by comparison of a full model (covariates + RPS) score to a reduced model (covariates only). For clarity, 3 different P value thresholds (_P_T) are presented denoted by the colour of each bar (legend above plot) as for Extended Data Fig. 5, but for clarity we restrict to fewer P value thresholds (_P_T of 5 × 10−8, 1 × 10−4 and 0.05) and removed the significance values. b, The proportion of variance on the liability scale from risk scores calculated at the _P_T 0.05 with 95% CI bar assuming baseline population disease risk of 1%. c, Area under the receiver operating curve (AUC). All numerical data and methods used to generate these plots are available in Supplementary Table 7 and Supplementary Methods.

Extended Data Table 1 ALIGATOR and INRICH

Full size table

Extended Data Table 2 de novo overlap

Full size table

Supplementary information

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. (PDF 1772 kb)

Supplementary Figure

This file contains Supplementary Figure 1. (PDF 2168 kb)

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. (XLSX 106 kb)

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). (XLS 173 kb)

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. (XLS 96 kb)

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. (XLS 32 kb)

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Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci.Nature 511, 421–427 (2014). https://doi.org/10.1038/nature13595

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