Article

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression

  • Nature Geneticsvolume 50pages668681 (2018)
  • doi:10.1038/s41588-018-0090-3
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Abstract

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

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Acknowledgements

Full acknowledgments are in the Supplementary Note. We are deeply indebted to the investigators who comprise the PGC, and to the hundreds of thousands of subjects who have shared their life experiences with PGC investigators. A full list of funding is in the Supplementary Note. Major funding for the PGC is from the US National Institutes of Health (U01 MH109528 and U01 MH109532). Statistical analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org/) hosted by SURFsara. The iPSYCH team acknowledges funding from the Lundbeck Foundation (grants R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project 294838), the Novo Nordisk Foundation for supporting the Danish National Biobank resource, and Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center. This research has been conducted using the UK Biobank Resource (see URLs), including applications 4844 and 6818. Finally, we thank the members of the eQTLGen Consortium for allowing us to use their very large eQTL database ahead of publication. Its members are listed in Supplementary Table 14.

Some data used in this study were obtained from dbGaP (see URLs). dbGaP accession phs000021: funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469, and U01 MH79470), and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (principal investigator P. V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, IL, USA). dbGaP accession phs000196: this work used in part data from the NINDS dbGaP database from the CIDR:NGRC PARKINSON’S DISEASE STUDY. dbGaP accession phs000187: High-Density SNP Association Analysis of Melanoma: Case–Control and Outcomes Investigation. Research support to collect data and develop an application to support this project was provided by P50 CA093459, P50 CA097007, R01 ES011740, and R01 CA133996 from the NIH.

Author information

Author notes

  1. A full list of members and affiliations appears in Supplementary Table 14.

  2. These authors contributed equally: Naomi R. Wray, Stephan Ripke, Manuel Mattheisen, Maciej Trzaskowski

  3. These authors jointly directed this work: Cathryn M. Lewis, Douglas F. Levinson, Gerome Breen, Anders D. Børglum, Patrick F. Sullivan.

Affiliations

  1. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    • Naomi R. Wray
    • , Maciej Trzaskowski
    • , Enda M. Byrne
    • , Grant W. Montgomery
    • , Peter M. Visscher
    • , Yang Wu
    • , Jian Yang
    •  & Futao Zhang
  2. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    • Naomi R. Wray
    • , Baptiste Couvy-Duchesne
    • , Robert M. Maier
    • , Divya Mehta
    • , Peter M. Visscher
    •  & Jian Yang
  3. Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • Stephan Ripke
    • , Hassan S. Dashti
    • , Jacqueline M. Lane
    • , Richa Saxena
    •  & Tõnu Esko
  4. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Stephan Ripke
  5. Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany

    • Stephan Ripke
    • , Julia Kraft
    •  & Vassily Trubetskoy
  6. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    • Manuel Mattheisen
    • , Jane Hvarregaard Christensen
    • , Jakob Grove
    • , Per Qvist
    •  & Anders D. Børglum
  7. iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark

    • Manuel Mattheisen
    • , Henriette N. Buttenschøn
    • , Jane Hvarregaard Christensen
    • , Jakob Grove
    • , Per Qvist
    • , Preben Bo Mortensen
    •  & Anders D. Børglum
  8. iPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    • Manuel Mattheisen
    • , Esben Agerbo
    • , Marie Bækvad-Hansen
    • , Henriette N. Buttenschøn
    • , Jonas Bybjerg-Grauholm
    • , Jane Hvarregaard Christensen
    • , Jakob Grove
    • , Christine Søholm Hansen
    • , David M. Hougaard
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    • , Per Qvist
    • , Wesley Thompson
    • , Yunpeng Wang
    • , Shantel Marie Weinsheimer
    • , Ole Mors
    • , Preben Bo Mortensen
    • , Merete Nordentoft
    • , Thomas Werge
    •  & Anders D. Børglum
  9. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    • Manuel Mattheisen
  10. Department of Biological Psychology and EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Abdel Abdellaoui
    • , Conor V. Dolan
    • , Jouke-Jan Hottenga
    • , Hamdi Mbarek
    • , Christel M. Middeldorp
    • , Michel G. Nivard
    • , Gonneke Willemsen
    • , Dorret I. Boomsma
    •  & E. C. J. de Geus
  11. Division of Psychiatry, University of Edinburgh, Edinburgh, UK

    • Mark J. Adams
    • , Douglas R. H. Blackwood
    • , Toni-Kim Clarke
    • , Lynsey S. Hall
    •  & Andrew M. McIntosh
  12. Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    •  & Preben Bo Mortensen
  13. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    •  & Preben Bo Mortensen
  14. Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia

    • Tracy M. Air
    •  & Bernhard T. Baune
  15. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    • Till M. F. Andlauer
    • , Elisabeth B. Binder
    •  & Bertram Müller-Myhsok
  16. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    • Till M. F. Andlauer
    •  & Bertram Müller-Myhsok
  17. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    • Silviu-Alin Bacanu
    • , Tim B. Bigdeli
    • , Roseann E. Peterson
    • , Brien P. Riley
    •  & Kenneth S. Kendler
  18. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    • Marie Bækvad-Hansen
    • , Jonas Bybjerg-Grauholm
    • , Christine Søholm Hansen
    •  & David M. Hougaard
  19. Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, The Netherlands

    • Aartjan F. T. Beekman
    • , Rick Jansen
    • , Yuri Milaneschi
    • , Wouter J. Peyrot
    • , Johannes H. Smit
    •  & Brenda W. J. H. Penninx
  20. Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, USA

    • Tim B. Bigdeli
  21. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA

    • Elisabeth B. Binder
  22. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Julien Bryois
    • , Erik Pettersson
    • , Alexander Viktorin
    • , Patrik K. Magnusson
    • , Nancy L. Pedersen
    •  & Patrick F. Sullivan
  23. Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark

    • Henriette N. Buttenschøn
  24. Statistical Genomics and Systems Genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK

    • Na Cai
  25. Human Genetics, Wellcome Trust Sanger Institute, Cambridge, UK

    • Na Cai
  26. Department of Psychiatry, University Hospital of Lausanne, Prilly, Switzerland

    • Enrique Castelao
    • , Giorgio Pistis
    •  & Martin Preisig
  27. MRC Social Genetic and Developmental Psychiatry Centre, King’s College London, London, UK

    • Jonathan I. R. Coleman
    • , Thalia C. Eley
    • , Héléna A. Gaspar
    • , Peter McGuffin
    • , Niamh Mullins
    • , Paul F. O’Reilly
    • , Margarita Rivera
    • , Cathryn M. Lewis
    •  & Gerome Breen
  28. Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

    • Lucía Colodro-Conde
    • , Eske M. Derks
    • , Penelope A. Lind
    • , Sarah E. Medland
    •  & Jodie N. Painter
  29. Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia

    • Baptiste Couvy-Duchesne
  30. Psychological Medicine, Cardiff University, Cardiff, UK

    • Nick Craddock
  31. Center for Genomic and Computational Biology, Duke University, Durham, NC, USA

    • Gregory E. Crawford
  32. Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, USA

    • Gregory E. Crawford
  33. Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Cheynna A. Crowley
    •  & Yun Li
  34. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Hassan S. Dashti
    • , Jacqueline M. Lane
    •  & Richa Saxena
  35. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Gail Davies
    • , Ian J. Deary
    •  & Andrew M. McIntosh
  36. Institute of Human Genetics, University of Bonn, Bonn, Germany

    • Franziska Degenhardt
    • , Andreas J. Forstner
    • , Stefan Herms
    • , Per Hoffmann
    • , Sven Cichon
    •  & Markus M. Nöthen
  37. Life & Brain Center, Department of Genomics, University of Bonn, Bonn, Germany

    • Franziska Degenhardt
    • , Andreas J. Forstner
    • , Stefan Herms
    • , Per Hoffmann
    •  & Markus M. Nöthen
  38. Psychiatry, Dokuz Eylul University School of Medicine, Izmir, Turkey

    • Nese Direk
  39. Epidemiology, Erasmus MC, Rotterdam, The Netherlands

    • Nese Direk
    • , Saira Saeed Mirza
    •  & Henning Tiemeier
  40. Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA

    • Erin C. Dunn
    •  & Jordan W. Smoller
  41. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Erin C. Dunn
    • , Roy H. Perlis
    •  & Jordan W. Smoller
  42. Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA

    • Erin C. Dunn
    •  & Jordan W. Smoller
  43. Research, 23andMe, Inc., Mountain View, CA, USA

    • Nicholas Eriksson
    • , Chao Tian
    •  & David A. Hinds
  44. Neuroscience and Mental Health, Cardiff University, Cardiff, UK

    • Valentina Escott-Price
  45. Bioinformatics, University of British Columbia, Vancouver, British Columbia, Canada

    • Farnush Hassan Farhadi Kiadeh
  46. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    • Hilary K. Finucane
  47. Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Hilary K. Finucane
  48. Department of Psychiatry (UPK), University of Basel, Basel, Switzerland

    • Andreas J. Forstner
  49. Human Genomics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland

    • Andreas J. Forstner
    • , Stefan Herms
    • , Per Hoffmann
    •  & Sven Cichon
  50. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    • Josef Frank
    • , Fabian Streit
    • , Jana Strohmaier
    • , Jens Treutlein
    • , Stephanie H. Witt
    • , Marcella Rietschel
    •  & Thomas G. Schulze
  51. Department of Psychiatry, Trinity College Dublin, Dublin, Ireland

    • Michael Gill
  52. Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Paola Giusti-Rodríguez
    • , Yun Li
    •  & Patrick F. Sullivan
  53. Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA

    • Fernando S. Goes
    • , Dean F. MacKinnon
    • , Francis M. Mondimore
    • , J. Raymond DePaulo
    •  & Thomas G. Schulze
  54. Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Scott D. Gordon
    •  & Nicholas G. Martin
  55. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    • Jakob Grove
  56. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK

    • Lynsey S. Hall
  57. University of Exeter Medical School, Exeter, UK

    • Eilis Hannon
    •  & Jonathan Mill
  58. Danish Headache Centre, Department of Neurology, Rigshospitalet, Glostrup, Denmark

    • Thomas F. Hansen
  59. Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark

    • Thomas F. Hansen
    • , Wesley Thompson
    • , Yunpeng Wang
    • , Shantel Marie Weinsheimer
    •  & Thomas Werge
  60. iPSYCH, Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark

    • Thomas F. Hansen
  61. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia

    • Ian B. Hickie
  62. Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany

    • Georg Homuth
  63. Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann–La Roche, Ltd, Basel, Switzerland

    • Carsten Horn
  64. Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    • Ming Hu
  65. Statistics, Pfizer Global Research and Development, Groton, CT, USA

    • Craig L. Hyde
  66. Max Planck Institute of Psychiatry, Munich, Germany

    • Marcus Ising
    • , Stefan Kloiber
    •  & Susanne Lucae
  67. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    • Fulai Jin
  68. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    • Fulai Jin
    • , Xiaoxiao Liu
    •  & Leina Lu
  69. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA

    • Eric Jorgenson
    • , Ling Shen
    •  & Catherine Schaefer
  70. Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA

    • James A. Knowles
  71. Informatics Program, Boston Children’s Hospital, Boston, MA, USA

    • Isaac S. Kohane
  72. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Isaac S. Kohane
  73. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

    • Isaac S. Kohane
  74. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • Warren W. Kretzschmar
    •  & Yihan Li
  75. Department of Endocrinology at Herlev University Hospital, University of Copenhagen, Copenhagen, Denmark

    • Jesper Krogh
  76. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    • Zoltán Kutalik
  77. Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, Switzerland

    • Zoltán Kutalik
  78. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Jacqueline M. Lane
    •  & Richa Saxena
  79. Mental Health, NHS 24, Glasgow, UK

    • Donald J. MacIntyre
  80. Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    • Donald J. MacIntyre
  81. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    • Wolfgang Maier
  82. Statistics, University of Oxford, Oxford, UK

    • Jonathan Marchini
  83. Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA

    • Patrick McGrath
    •  & Myrna M. Weissman
  84. School of Psychology and Counseling, Queensland University of Technology, Brisbane, Queensland, Australia

    • Divya Mehta
  85. Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Service, South Brisbane, Queensland, Australia

    • Christel M. Middeldorp
  86. Child Health Research Centre, University of Queensland, Brisbane, Queensland, Australia

    • Christel M. Middeldorp
  87. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Evelin Mihailov
    • , Lili Milani
    • , Tõnu Esko
    •  & Andres Metspalu
  88. Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

    • Sara Mostafavi
  89. Statistics, University of British Columbia, Vancouver, British Columbia, Canada

    • Sara Mostafavi
    •  & Bernard Ng
  90. DZHK (German Centre for Cardiovascular Research), partner site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Germany

    • Matthias Nauck
  91. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany

    • Matthias Nauck
  92. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

    • Dale R. Nyholt
  93. Humus, Reykjavik, Iceland

    • Hogni Oskarsson
  94. MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK

    • Michael J. Owen
    •  & Michael C. O’Donovan
  95. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Roseann E. Peterson
  96. Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Danielle Posthuma
  97. Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    • Danielle Posthuma
  98. Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA

    • Shaun M. Purcell
  99. Solid Biosciences, Boston, MA, USA

    • Jorge A. Quiroz
  100. Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA

    • John P. Rice
    • , Andrew C. Heath
    •  & Pamela F. A. Madden
  101. Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain

    • Margarita Rivera
  102. Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    • Robert Schoevers
  103. Department of Psychiatry and Psychotherapy, Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany

    • Eva C. Schulte
  104. Institute of Psychiatric Phenomics and Genomics (IPPG), Medical Center of the University of Munich, Campus Innenstadt, Munich, Germany

    • Eva C. Schulte
    •  & Thomas G. Schulze
  105. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

    • Jianxin Shi
  106. Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, USA

    • Stanley I. Shyn
  107. Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, Iceland

    • Engilbert Sigurdsson
  108. School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia

    • Grant B. C. Sinnamon
  109. Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK

    • Daniel J. Smith
  110. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland

    • Hreinn Stefansson
    • , Stacy Steinberg
    • , Thorgeir E. Thorgeirsson
    •  & Kari Stefansson
  111. Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

    • Craig A. Stockmeier
  112. College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK

    • Katherine E. Tansey
  113. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany

    • Henning Teismann
    • , Jürgen Wellmann
    •  & Klaus Berger
  114. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    • Alexander Teumer
    •  & Henry Völzke
  115. KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Wesley Thompson
    •  & Yunpeng Wang
  116. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    • Wesley Thompson
  117. Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, UK

    • Pippa A. Thomson
    •  & David J. Porteous
  118. Clinical Neurosciences, University of Cambridge, Cambridge, UK

    • Matthew Traylor
  119. Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

    • André G. Uitterlinden
  120. Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann–La Roche, Ltd, Basel, Switzerland

    • Daniel Umbricht
  121. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

    • Sandra Van der Auwera
    •  & Hans J. Grabe
  122. Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands

    • Albert M. van Hemert
  123. Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Bradley T. Webb
  124. Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, USA

    • Hualin S. Xi
  125. Department of Psychiatry, University of Münster, Munster, Germany

    • Volker Arolt
    •  & Udo Dannlowski
  126. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany

    • Sven Cichon
  127. Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland

    • Sven Cichon
  128. Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    • E. C. J. de Geus
  129. Centre for Integrative Biology, Università degli Studi di Trento, Trento, Italy

    • Enrico Domenici
  130. Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    • Katharina Domschke
  131. Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, USA

    • Steven P. Hamilton
  132. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Caroline Hayward
  133. Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    • Stefan Kloiber
  134. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    • Stefan Kloiber
  135. Division of Psychiatry, University College London, London, UK

    • Glyn Lewis
  136. Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA

    • Qingqin S. Li
  137. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

    • Andres Metspalu
  138. Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Denmark

    • Ole Mors
  139. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    • Bertram Müller-Myhsok
  140. Mental Health Center Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    • Merete Nordentoft
  141. Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, USA

    • Sara A. Paciga
  142. Psychiatry, Harvard Medical School, Boston, MA, USA

    • Roy H. Perlis
  143. Psychiatry, University of Iowa, Iowa City, IA, USA

    • James B. Potash
  144. Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA

    • Thomas G. Schulze
  145. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

    • Thomas G. Schulze
  146. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Kari Stefansson
  147. Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, The Netherlands

    • Henning Tiemeier
  148. Psychiatry, Erasmus MC, Rotterdam, The Netherlands

    • Henning Tiemeier
  149. Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada

    • Rudolf Uher
  150. Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA

    • Myrna M. Weissman
  151. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Thomas Werge
  152. Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Cambridge, MA, USA

    • Ashley R. Winslow
  153. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Ashley R. Winslow
  154. Department of Medical and Molecular Genetics, King’s College London, London, UK

    • Cathryn M. Lewis
  155. Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    • Douglas F. Levinson
  156. NIHR BRC for Mental Health, King’s College London, London, UK

    • Gerome Breen
  157. Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Patrick F. Sullivan

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Consortia

  1. eQTLGen

    1. 23andMe

      1. the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

        Contributions

        Writing group: G.B., A.D.B., D.F.L., C.M.L., S.R., P.F.S., N.R.W. PGC MDD PI group: V.A., B.T.B., K.B., D.I.B., G.B., A.D.B., S.C., U.D., J.R.D., E.D., K.D., T.E., E.J.C.d.G., H.J.G., S.P.H., C. Hayward, A.C.H., D.M.H., K.S.K., S.K., D.F.L., C.M.L., G.L., Q.S.L., S.L., P.A.F.M., P.K.M., N.G.M., A.M.M., A.M., O.M., P.B.M., B.M.-M., M. Nordentoft, M.M.N., M.C.O’D., S.A.P., N.L.P., B.W.P., R.H.P., D.J.P., J.B.P., M.P., M. Rietschel, C.S., T.G.S., J.W.S., K.S., P.F.S., H. Tiemeier, R.U., H.V., M.M.W., T.W., A.R.W., N.R.W. Bioinformatics: 23andMe Research Team, M.J.A., S.V.d.A., G.B., J.B., A.D.B., E.C., J.H.C., T.-K.C., J.R.I.C., L.C.-C., eQTLGen Consortium, G.E.C., C.A.C., G.D., E.M.D., T.E., A.J.F., H.A.G., P.G.-R., J.G., L.S.H., E.H., T.F.H., C. Hayward, M.H., R.J., F.J., Z.K., Q.S.L., Yihan Li, P.A.L., X.L., L.L., D.J.M., S.E.M., E.M., Y.M., J. Mill, J.N.P., B.W.P., W.J.P., G.P., P.Q., L.S., S.I.S., C.A.S., P.F.S., K.E.T., A.T., P.A.T., A.G.U., Y. Wang, S.M.W., N.R.W., H.S.X. Clinical: E.A., T.M.A., V.A., B.T.B., A.T.F.B., K.B., E.B.B., D.H.R.B., H.N.B., A.D.B., N. Craddock, U.D., J.R.D., N.D., K.D., M.G., F.S.G., H.J.G., A.C.H., A.M.v.H., I.B.H., M.I., S.K., J. Krogh, D.F.L., S.L., D.J.M., D.F.M., P.A.F.M., W.M., N.G.M., P. McGrath, P. McGuffin, A.M.M., A.M., C.M.M., S.S.M., F.M.M., O.M., P.B.M., D.R.N., H.O., M.J.O., C.B.P., M.G.P., J.B.P., J.A.Q., J.P.R., M. Rietschel, C.S., R. Schoevers, E.S., G.C.B.S., D.J.S., F.S., J. Strohmaier, D.U., M.M.W., J.W., T.W., G.W. Genomic assays: G.B., H.N.B., J.B.-G., M.B.-H., A.D.B., S.C., T.-K.C., F.D., A.J.F., S.P.H., C.S.H., A.C.H., P.H., G.H., C. Horn, J.A.K., P.A.F.M., L.M., G.W.M., M. Nauck, M.M.N., M. Rietschel, M. Rivera, E.C.S., T.G.S., S.I.S., H.S., F.S., T.E.T., J.T., A.G.U., S.H.W. Obtained funding for primary MDD samples: B.T.B., K.B., D.H.R.B., D.I.B., G.B., H.N.B., A.D.B., S.C., J.R.D., I.J.D., E.D., T.C.E., T.E., H.J.G., S.P.H., A.C.H., D.M.H., I.S.K., D.F.L., C.M.L., G.L., Q.S.L., S.L., P.A.F.M., W.M., N.G.M., P. McGuffin, A.M.M., A.M., G.W.M., O.M., P.B.M., M. Nordentoft, D.R.N., M.M.N., P.F.O’R., B.W.P., D.J.P., J.B.P., M.P., M. Rietschel, C.S., T.G.S., G.C.B.S., J.H.S., D.J.S., H.S., K.S., P.F.S., T.E.T., H. Tiemeier, A.G.U., H.V., M.M.W., T.W., N.R.W. Statistical analysis: 23andMe Research Team, A.A., M.J.A., T.F.M.A., S.V.d.A., S.-A.B., K.B., T.B.B., G.B., E.M.B., A.D.B., N. Cai, T.-K.C., J.R.I.C., B.C.-D., H.S.D., G.D., N.D., C.V.D., E.C.D., N.E., V.E.-P., T.E., H.K.F., J.F., H.A.G., S.D.G., J.G., L.S.H., C. Hayward, A.C.H., S.H., D.A.H., J.-J.H., C.L.H., M.I., E.J., F.F.H.K., J. Kraft, W.W.K., Z.K., J.M.L., C.M.L., Q.S.L., Yun Li, D.J.M., P.A.F.M., R.M.M., J. Marchini, M.M., H.M., A.M.M., S.E.M., D.M., E.M., Y.M., S.S.M., S.M., N.M., B.M.-M., B.N., M.G.N., D.R.N., P.F.O’R., R.E.P., E.P., W.J.P., G.P., D.P., S.M.P., B.P.R., S.R., M. Rivera, R. Saxena, C.S., L.S., J. Shi, S.I.S., H.S., S.S., P.F.S., K.E.T., H. Teismann, A.T., W.T., P.A.T., T.E.T., C.T., M. Traylor, V.T., M. Trzaskowski, A.V., P.M.V., Y. Wang, B.T.W., J.W., T.W., N.R.W., Y. Wu, J.Y., F.Z.

        Competing interests

        A.T.F.B. is on speaker’s bureaus for Lundbeck and GlaxoSmithKline. G.C. is a cofounder of Element Genomics. E.D. was an employee of Hoffmann–La Roche at the time this study was conducted and a consultant to Roche and Pierre-Fabre. N.E. is employed by 23andMe, Inc., and owns stock in 23andMe, Inc. D.H. is an employee of and owns stock options in 23andMe, Inc. S.P. is an employee of Pfizer, Inc. C.L.H. is an employee of Pfizer, Inc. A.R.W. was a former employee and stockholder of Pfizer, Inc. J.A.Q. was an employee of Hoffmann–La Roche at the time this study was conducted. H.S. is an employee of deCODE Genetics/Amgen. K.S. is an employee of deCODE Genetics/Amgen. S.S. is an employee of deCODE Genetics/Amgen. P.F.S. is on the scientific advisory board for Pfizer, Inc., and the advisory committee for Lundbeck. T.E.T. is an employee of deCODE Genetics/Amgen. C.T. is an employee of and owns stock options in 23andMe, Inc.

        Corresponding authors

        Correspondence to Naomi R. Wray or Patrick F. Sullivan.

        Supplementary information

        1. Supplementary Text and Figures

          Supplementary Figures 1–4 and Supplementary Note

        2. Reporting Summary

        3. Supplementary Tables

          Supplementary Tables 1–15

        4. Supplementary Data 1

          Regional association plots of the 44 regions with genome-wide significant loci associated with major depression. Association test from meta-analysis of 135,458 major depression cases and 344,901 controls.

        5. Supplementary Data 2

          Regional association plots of genomic regions identified from SMR analysis of major depression genome-wide association and eQTL results. SMR analysis helps to prioritize specific genes in a region of association for follow-up functional studies. Figures appear in the same order as the results reported in Supplementary Table 9. In the top plot, gray dots represent the major depression genome-wide association P values, diamonds show P values for probes from the SMR test, and triangles are probes without a cis-eQTL (at PeQTL < 5 × 10–8). Genes that pass SMR and heterogeneity tests (designed to remove loci with more than one causal association) are highlighted in red. The eQTL P values of SNPs are shown in the bottom plot.