Article | Published:

Gene expression imputation across multiple brain regions provides insights into schizophrenia risk

Nature Geneticsvolume 51pages659674 (2019) | Download Citation

Abstract

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.

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Data availability

Our CMC-derived DLPFC prediction models are publicly available at https://github.com/laurahuckins/CMC_DLPFC_prediXcan.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 13 May 2019

    In the HTML version of the article originally published, the author group ‘The Schizophrenia Working Group of the Psychiatric Genomics Consortium’ was displayed incorrectly. The error has been corrected in the HTML version of the article.

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Acknowledgements

We dedicate this manuscript to the memory of Pamela Sklar, whose guidance and wisdom we miss daily. We strive to continue her legacy of thoughtful, innovative, and collaborative science. Data were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited, F. Hoffman-La Roche Ltd and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881 and R37MH057881S1, HHSN271201300031C, AG02219, AG05138 and MH06692.

Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh NeuroBioBank and Brain and Tissue Repositories and the NIMH Human Brain Collection Core. CMC Leadership: P. Sklar, J. Buxbaum (Icahn School of Medicine at Mount Sinai), B. Devlin, D. Lewis (University of Pittsburgh), R. Gur, C.-G. Hahn (University of Pennsylvania), K. Hirai, H. Toyoshiba (Takeda Pharmaceuticals Company Limited), E. Domenici, L. Essioux (F. Hoffman-La Roche Ltd), L. Mangravite, M. Peters (Sage Bionetworks), T. Lehner, B. Lipska (NIMH).

ROSMAP study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute.

The iPSYCH-GEMS team acknowledges funding from the Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, an Advanced Grant from the European Research Council (project no. 294838), the Danish Strategic Research Council the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center.

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on September 5, 2016. BrainSpan: Atlas of the Developing Human Brain (Internet). Funded by ARRA Awards 1RC2MH089921-01, 1RC2MH090047-01, and 1RC2MH089929-01.

H.K.I. was supported by R01 MH107666-01.

Author information

Affiliations

  1. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Laura M. Huckins
    • , Amanda Dobbyn
    • , Gabriel Hoffman
    • , Weiqing Wang
    • , Hoang T. Nguyen
    • , Kiran Girdhar
    • , Panos Roussos
    • , Menachem Fromer
    • , Shaun Purcell
    • , Jessica S. Johnson
    • , Vahram Haroutunian
    • , Menachem Fromer
    • , Shaun M. Purcell
    • , Panos Roussos
    • , Douglas M. Ruderfer
    • , Eli A. Stahl
    • , Pamela Sklar
    • , Pamela Sklar
    •  & Eli A. Stahl
  2. Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Laura M. Huckins
    • , Amanda Dobbyn
    • , Weiqing Wang
    • , Hoang T. Nguyen
    • , Kiran Girdhar
    • , Panos Roussos
    • , Menachem Fromer
    • , Shaun Purcell
    • , Hardik R. Shah
    • , Milind C. Mahajan
    • , Eric Schadt
    • , Guiqing Cai
    • , Eli A. Stahl
    • , Joseph D. Buxbaum
    • , Pamela Sklar
    • , Pamela Sklar
    •  & Eli A. Stahl
  3. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Laura M. Huckins
    • , Panos Roussos
    • , Guiqing Cai
    • , Kenneth L. Davis
    • , Elodie Drapeau
    • , Joseph I. Friedman
    • , Vahram Haroutunian
    • , Elena Parkhomenko
    • , Abraham Reichenberg
    • , Jeremy M. Silverman
    • , Eli A. Stahl
    • , Joseph D. Buxbaum
    • , Pamela Sklar
    • , Pamela Sklar
    •  & Eli A. Stahl
  4. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Laura M. Huckins
    • , Gabriel Hoffman
    • , Panos Roussos
    • , Shaun Purcell
    • , Hardik R. Shah
    • , Milind C. Mahajan
    • , Eric Schadt
    • , Panos Roussos
    • , Eli A. Stahl
    • , Pamela Sklar
    • , Pamela Sklar
    •  & Eli A. Stahl
  5. Vanderbilt University Medical Center, Nashville, TN, USA

    • Douglas M. Ruderfer
    • , Eric R. Gamazon
    • , Douglas M. Ruderfer
    •  & Nancy J. Cox
  6. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    • Antonio F. Pardiñas
    • , 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
    • , James T. R. Walters
    • , Michael C. O’Donovan
    •  & Michael J. Owen
  7. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    • Veera M. Rajagopal
    • , Thomas D. Als
    • , Ditte Demontis
    • , Manuel Mattheisen
    • , Anders D. Børglum
    • , Anders D. Børglum
    • , Ditte Demontis
    • , Veera Manikandan Rajagopal
    • , Thomas D. Als
    • , Manuel Mattheisen
    • , Jakob Grove
    • , Preben Bo Mortensen
    • , Ditte Demontis
    •  & Anders D. Børglum
  8. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark

    • Veera M. Rajagopal
    • , Thomas D. Als
    • , Esben Agerbo
    • , Ditte Demontis
    • , Thomas Hansen
    • , Manuel Mattheisen
    • , Ole Mors
    • , Line Olsen
    • , Anders D. Børglum
    • , Preben B. Mortensen
    • , Thomas Werge
    • , Anders D. Børglum
    • , Ditte Demontis
    • , Veera Manikandan Rajagopal
    • , Thomas D. Als
    • , Manuel Mattheisen
    • , Jakob Grove
    • , Thomas Werge
    • , Preben Bo Mortensen
    • , Carsten Bøcker Pedersen
    • , Esben Agerbo
    • , Marianne Giørtz Pedersen
    • , Ole Mors
    • , Merete Nordentoft
    • , David M. Hougaard
    • , Jonas Bybjerg-Grauholm
    • , Marie Bækvad-Hansen
    • , Christine Søholm Hansen
    • , Ditte Demontis
    •  & Anders D. Børglum
  9. Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark

    • Veera M. Rajagopal
    • , Thomas D. Als
    • , Ditte Demontis
    • , Manuel Mattheisen
    • , Ole Mors
    • , Anders D. Børglum
    • , Anders D. Børglum
    • , Ditte Demontis
    • , Veera Manikandan Rajagopal
    • , Thomas D. Als
    • , Manuel Mattheisen
    • , Jakob Grove
    • , Ditte Demontis
    •  & Anders D. Børglum
  10. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    • James Boocock
    • , Rita M. Cantor
    •  & Roel A. Ophoff
  11. Human Brain Collection Core, National Institute of Mental Health, Bethesda, MD, USA

    • Robin Kramer
    •  & Barbara K. Lipska
  12. Laboratory of Neurogenomic Biomarkers, Centre for Integrative Biology (CIBIO), University of Trento, Trento, Italy

    • Enrico Domenici
  13. Clare Hall, University of Cambridge, Cambridge, UK

    • Eric R. Gamazon
  14. University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Wei Cheng
    •  & Patrick Sullivan
  15. Karolinska Institutet, Stockholm, Sweden

    • Patrick Sullivan
  16. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

    • Lambertus L. Klein
    • , David A. Lewis
    •  & Bernie Devlin
  17. Systems Biology, Sage Bionetworks, Seattle, WA, USA

    • Kristen K. Dang
    • , Benjamin A. Logsdon
    • , Lara M. Mangravite
    • , Vahram Haroutunian
    • , Mette A. Peters
    • , Thanneer M. Perumal
    •  & Solveig K. Sieberts
  18. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA

    • Hae Kyung Im
  19. Integrated Technology Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan

    • Hiroyoshi Toyoshiba
  20. Neuropsychiatry Section, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Raquel E. Gur
  21. Neuropsychiatric Signaling Program, Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Chang-Gyu Hahn
  22. Psychiatry, JJ Peters Virginia Medical Center, Bronx, NY, USA

    • Vahram Haroutunian
    •  & Vahram Haroutunian
  23. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, NY, USA

    • Vahram Haroutunian
    •  & Joseph D. Buxbaum
  24. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Joseph D. Buxbaum
    • , Vahram Haroutunian
    • , Joseph D. Buxbaum
    •  & Pamela Sklar
  25. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Joseph D. Buxbaum
  26. CNS Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan

    • Keisuke Hirai
  27. F. Hoffman-La Roche Ltd, Basel, Switzerland

    • Laurent Essioux
  28. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    • Jakob Grove
  29. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    • Thomas Hansen
    • , Henrik B. Rasmussen
    • , Thomas Werge
    •  & Thomas Werge
  30. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Thomas Werge
  31. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Preben B. Mortensen
    • , Preben Bo Mortensen
    • , Carsten Bøcker Pedersen
    • , Esben Agerbo
    •  & Marianne Giørtz Pedersen
  32. Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Preben B. Mortensen
    • , Preben Bo Mortensen
    • , Carsten Bøcker Pedersen
    • , Esben Agerbo
    •  & Marianne Giørtz Pedersen
  33. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

    • Ole Mors
  34. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

    • Merete Nordentoft
  35. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    • Mads V. Hollegaard
    • , David M. Hougaard
    • , David M. Hougaard
    • , Jonas Bybjerg-Grauholm
    • , Marie Bækvad-Hansen
    •  & Christine Søholm Hansen
  36. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

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

    • Benjamin M. Neale
    • , Hailiang Huang
    • , Tune H. Pers
    • , Jacqueline I. Goldstein
    • , Joel N. Hirschhorn
    • , Alkes Price
    • , Tonu Esko
    •  & Mark J. Daly
  39. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

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

    • Aiden Corvin
    • , Paul Cormican
    • , Gary Donohoe
    • , Derek W. Morris
    •  & Michael Gill
  41. NationalCentre for Mental Health, Cardiff University, Cardiff, UK

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

    • David A. Collier
    • , Younes Mokrab
    •  & Henrik B. Rasmussen
  43. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK

    • David A. Collier
  44. Center for BiologicalSequence Analysis, Department of Systems Biology, Technical University of Denmark, Kongens Lyngby, Denmark

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

    • Tune H. Pers
    • , Joel N. Hirschhorn
    •  & Tonu Esko
  46. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden

    • Ingrid Agartz
    • , Erik Soderman
    •  & Erik G. Jonsson
  47. Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway

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

    • Ingrid Agartz
    • , Srdjan Djurovic
    • , Morten Mattingsdal
    • , Ingrid Melle
    • , Ole A. Andreassen
    •  & Erik G. Jonsson
  49. State Mental Hospital, Haar, Germany

    • Margot Albus
  50. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

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

    • Farooq Amin
  52. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

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

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

    • Martin Begemann
    • , Christian Hammer
    • , Sergi Papiol
    •  & Hannelore Ehrenreich
  55. Department of Medical Genetics, University of Pécs, Pécs, Hungary

    • Judit Bene
    •  & Bela Melegh
  56. Szentagothai Research Center, University of Pécs, Pécs, Hungary

    • Judit Bene
    •  & Bela Melegh
  57. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

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

    • Donald W. Black
  59. University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands

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

    • Nancy G. Buccola
  61. Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, MA, USA

    • Randy L. Buckner
    •  & Joshua L. Roffman
  62. Center for Brain Science, Harvard University, Cambridge, MA, USA

    • Randy L. Buckner
  63. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Randy L. Buckner
    • , Line Olsen
    •  & Joshua L. Roffman
  64. Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA

    • William Byerley
  65. University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands

    • Wiepke Cahn
    • , Rene S. Kahn
    • , Eric Strengman
    •  & Roel A. Ophoff
  66. Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France

    • Dominique Campion
  67. Schizophrenia Research Institute, Sydney, New South Wales, 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
  68. School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia

    • Vaughan J. Carr
  69. Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Queensland, Australia

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

    • Raymond C. K. Chan
  71. 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
  72. 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
  73. Castle Peak Hospital, Hong Kong, China

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

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

    • C. Robert Cloninger
    •  & Dragan M. Svrakic
  76. 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, France

    • David Cohen
  77. Blue Note Biosciences, Princeton, NJ, USA

    • Nadine Cohen
  78. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

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

    • David Curtis
  80. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK

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

    • Michael Davidson
    •  & Mark Weiser
  82. Department of Genomics, Life and Brain Center, Bonn, Germany

    • Franziska Degenhardt
    • , Stefan Herms
    • , Per Hoffmann
    • , Andrea Hofman
    • , Sven Cichon
    •  & Markus M. Nothen
  83. Institute of Human Genetics, University of Bonn, Bonn, Germany

    • Franziska Degenhardt
    • , Stefan Herms
    • , Per Hoffmann
    • , Andrea Hofman
    • , Sven Cichon
    •  & Markus M. Nothen
  84. AppliedMolecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium

    • Jurgen Del Favero
  85. First Department of Psychiatry, University of Athens Medical School, Athens, Greece

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

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

    • Srdjan Djurovic
  88. 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
  89. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA

    • Jubao Duan
    • , Alan R. Sanders
    •  & Pablo V. Gejman
  90. Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, IL, USA

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

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

    • Naser Durmishi
  93. Department of Psychiatry, University of Regensburg, Regensburg, Germany

    • Peter Eichhammer
  94. Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland

    • Johan Eriksson
  95. Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki, Helsinki, Finland

    • Johan Eriksson
  96. National Institute for Health and Welfare, Helsinki, Finland

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

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

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

    • Ayman H. Fanous
  100. Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

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

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

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

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

    • Robert Freedman
    •  & Roel A. Ophoff
  105. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA

    • Nelson B. Freimer
  106. Department of Psychiatry, University of Halle, Halle, Germany

    • Marion Friedl
    • , Ina Giegling
    • , Annette M. Hartmann
    • , Bettina Konte
    •  & Dan Rujescu
  107. Department of Psychiatry, University of Munich, Munich, Germany

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

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

    • Vera Golimbet
  110. Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, NJ, USA

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

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

    • Lieuwe de Haan
    •  & Carin J. Meijer
  113. Illumina, La Jolla, CA, USA

    • Mark Hansen
  114. Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, New South Wales, Australia

    • Frans A. Henskens
  115. School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia

    • Frans A. Henskens
  116. Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland

    • Stefan Herms
    • , Per Hoffmann
    •  & Sven Cichon
  117. Department of Genetics, Harvard Medical School, Boston, MA, USA

    • Joel N. Hirschhorn
    • , Tonu Esko
    •  & Steven A. McCarroll
  118. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan

    • Masashi Ikeda
    •  & Nakao Iwata
  119. Regional Centre for Clinical Researchin Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway

    • Inge Joa
  120. Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain

    • Antonio Julia
    •  & Sara Marsal
  121. Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia

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

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

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

    • Matthew C. Keller
    •  & Jo Knight
  125. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    • James L. Kennedy
    • , Ann Olincy
    •  & Clement C. Zai
  126. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

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

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

    • Andrey Khrunin
    • , Svetlana Limborska
    •  & Petr Slominsky
  129. Latvian Biomedical Research and Study Centre, Riga, Latvia

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

    • James A. Knowles
    • , Michele T. Pato
    •  & Carlos N. Pato
  131. Faculty of Medicine, Vilnius University, Vilnius, Lithuania

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

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

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

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

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

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

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

    • Kung-Yee Liang
  139. Department of Psychiatry, Columbia University, New York, New York, NY, USA

    • Jeffrey Lieberman
    •  & T. Scott Stroup
  140. Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, New South Wales, Australia

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

    • Jan Lubinski
  142. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland

    • Jouko Lonnqvist
    •  & Jaana Suvisaari
  143. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    • Brion S. Maher
    •  & Larry J. Seidman
  144. Department of Psychiatry, University of Bonn, Bonn, Germany

    • Wolfgang Maier
  145. Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodénégératifs, Hôpital de la Pitiè-Salpêtrière, Paris, France

    • Jacques Mallet
  146. Department of Genomics Mathematics, University of Bonn, Bonn, Germany

    • Manuel Mattheisen
  147. Research Unit, Sørlandet Hospital, Kristiansand, Norway

    • Morten Mattingsdal
  148. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    • Robert W. McCarley
    • , Raquelle I. Mesholam-Gately
    •  & Tracey L. Petryshen
  149. VA Boston Health Care System, Brockton, MA, USA

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

    • Colm McDonald
  151. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Andrew M. McIntosh
  152. Division of Psychiatry, University of Edinburgh, Edinburgh, UK

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

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

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

    • Andres Metspalu
    • , Lili Milani
    • , Mari Nelis
    •  & Tonu Esko
  156. School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia

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

    • Vihra Milanova
  158. Department P, Aarhus University Hospital, Risskov, Denmark

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

    • Kieran C. Murphy
  160. King’s College London, London, UK

    • Robin M. Murray
    •  & John Powell
  161. Maastricht University Medical Centre, South Limburg Mental Health Research and TeachingNetwork, EURON, Maastricht, the Netherlands

    • Inez Myin-Germeys
    •  & Jim Van Os
  162. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    • Bertram Muller-Myhsok
  163. Max Planck Institute of Psychiatry, Munich, Germany

    • Bertram Muller-Myhsok
  164. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    • Bertram Muller-Myhsok
  165. Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany

    • Igor Nenadic
  166. Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia

    • Deborah A. Nertney
  167. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

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

    • Kristin K. Nicodemus
  169. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA

    • Laura Nisenbaum
  170. Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden

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

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

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

    • Sang-Yun Oh
  174. Institute of Psychiatry, King’s College London, London, UK

    • Jim Van Os
  175. Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Victoria, Australia

    • Christos Pantelis
  176. Department of Psychiatry, University of Helsinki, Helsinki, Finland

    • Tiina Paunio
  177. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland

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

    • Milica Pejovic-Milovancevic
  179. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    • Diana O. Perkins
    •  & Patrick F. Sullivan
  180. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland

    • Olli Pietiläinen
    •  & Aarno Palotie
  181. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    • Alkes Price
  182. Department of Psychiatry, University of Oxford, Oxford, UK

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

    • Mark A. Reimers
    •  & Aaron R. Wolen
  184. Pharma Therapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA

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

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

    • Sibylle G. Schwab
  187. Hunter New England Health Service, Newcastle, New South Wales, Australia

    • Rodney J. Scott
  188. School of Biomedical Sciences, University of Newcastle, Newcastle, New South Wales, Australia

    • Rodney J. Scott
  189. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

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

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

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

    • Jeremy M. Silverman
  193. WellcomeTrust Centre for Human Genetics, Oxford, UK

    • Chris C. A. Spencer
  194. deCODE Genetics, Reykjavik, Iceland

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

    • Elisabeth Stogmann
    •  & Fritz Zimprich
  196. Lieber Institute for Brain Development, Baltimore, MD, USA

    • Richard E. Straub
    •  & Daniel R. Weinberger
  197. Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands

    • Eric Strengman
  198. Berkshire Healthcare NHS Foundation Trust, Bracknell, UK

    • Srinivas Thirumalai
  199. Section of Psychiatry, University of Verona, Verona, Italy

    • Sarah Tosato
  200. Department of Psychiatry, University of Oulu, Oulu, Finland

    • Juha Veijola
  201. University Hospital of Oulu, Oulu, Finland

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

    • John Waddington
  203. Health Research Board, Dublin, Ireland

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

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

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

    • Xuebin Zheng
    •  & Jianjun Liu
  207. University College London, London, UK

    • Elvira Bramon
  208. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany

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

    • Ariel Darvasi
  210. NeuroscienceDiscovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland

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

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

    • Kenneth S. Kendler
    •  & Brien P. Riley
  213. The Feinstein Institute for Medical Research, Manhasset, NY, USA

    • Todd Lencz
    •  & Anil K. Malhotra
  214. The Hofstra NS-LIJ School of Medicine, Hempstead, NY, USA

    • Todd Lencz
    •  & Anil K. Malhotra
  215. The Zucker Hillside Hospital, Glen Oaks, NY, USA

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

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

    • Bryan J. Mowry
  218. Center for HumanGenetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Tracey L. Petryshen
  219. Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands

    • Danielle Posthuma
  220. Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, the Netherlands

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

    • Danielle Posthuma
  222. University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK

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

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

    • Thomas Werge

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Consortia

  1. CommonMind Consortium

  1. The Schizophrenia Working Group of the Psychiatric Genomics Consortium

  1. iPSYCH-GEMS Schizophrenia Working Group

Contributions

L.M.H. designed the study and specific subanalyses, ran analyses, and wrote the manuscript. A.D. designed and ran analyses and contributed to the writing group. D.M.R. contributed to study and analytical design, and writing. G.H. contributed to analytical design and writing. W.W., H.T.N., and J.B. designed and ran specific analyses. A.F.P., V.M.R., T.D.A., K.G., M.F. all ran specific analyses. S.K.S. designed the study and analyses and contributed to the writing group. P.R. and R.K. designed the study and contributed data. E.D. designed the study, contributed data, and contributed to the writing group. E.R.G. designed specific analyses, and contributed to the writing group. S.P. designed the study. All three consortia (CMC, PGC-SCZ, iPSYCH-GEMS) contributed data. D.D., A.D.B., J.T.R.W., M.C.O’D., M.J.O. contributed data, advised on analyses, and contributed to the writing group. P. Sullivan advised on analyses and contributed to the writing group. B.D. designed the study, contributed data, advised on analyses, and contributed to the writing group. N.J.C. and H.K.I. designed the study, advised on analyses, and contributed to the writing group. P. Sklar and E.A.S. designed the study and specific analyses, ran analyses, and contributed to the writing group.

Competing interests

E.D. has received research support from Roche during 2016–2018. T.W. has acted as advisor and lecturer to H. Lundbeck A/S. All other authors declare no conflicts of interest.

Corresponding author

Correspondence to Laura M. Huckins.

Supplementary information

  1. Supplementary Information

    Supplementary Note and Supplementary Figures 1–12

  2. Reporting Summary

  3. Supplementary Table 1

    Forward stepwise conditional analysis results.

  4. Supplementary Table 2

    MAGMA based pathway association results.

  5. Supplementary Table 3

    Mutant mouse lines lacking expression of SCZ-associated genes

  6. Supplementary Table 4

    Gene set membership of SCZ-associated genes, according to BRAINSPAN clusters

About this article

Publication history

Received

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41588-019-0364-4

Further reading