Article | Published:

Genome-wide association study identifies 30 loci associated with bipolar disorder

Nature Geneticsvolume 51pages793803 (2019) | Download Citation

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10−4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

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Data availability

The PGC’s policy is to make genome-wide summary results public. Summary statistics for our meta-analysis are available through the PGC (https://www.med.unc.edu/pgc/results-and-downloads). Data are accessible with collaborative analysis proposals through the Bipolar Disorder Working Group of the PGC (https://med.unc.edu/pgc).

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Acknowledgements

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar Disorder Working Group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org), hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu). PGC members have received major funding from the US National Institute of Mental Health. This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M. O’Neil and Betty C. Lynch. The views expressed are those of the authors and not necessarily those of their institutions or any funding or regulatory bodies. Additional acknowledgements, including funding sources, are presented in the Supplementary Note.

Author information

Author notes

  1. These authors contributed equally: Eli A Stahl, Gerome Breen, Andreas J Forstner, Andrew McQuillin, Stephan Ripke

  2. These authors jointly supervised this work: John Kelsoe, Pamela Sklar

  3. A list of members and affiliations appears in the Supplementary Note.

Affiliations

  1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Eli A. Stahl
    • , Amanda L. Dobbyn
    • , Laura Huckins
    • , Jessica S. Johnson
    • , Hoang Nguyen
    • , Panos Roussos
    • , Weiqing Wang
    •  & Pamela Sklar
  2. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Eli A. Stahl
    • , Alexander W. Charney
    • , Amanda L. Dobbyn
    • , Laura Huckins
    • , Jessica S. Johnson
    • , Hoang Nguyen
    • , Shaun M. Purcell
    • , Panos Roussos
    • , Weiqing Wang
    • , René S. Kahn
    •  & Pamela Sklar
  3. Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • Eli A. Stahl
    • , Tune H. Pers
    • , Tõnu Esko
    •  & Benjamin M. Neale
  4. MRC Social, Genetic and Developmental Psychiatry Centre, King’s College London, London, UK

    • Gerome Breen
    • , Jonathan R. I. Coleman
    • , Héléna A. Gaspar
    • , Simone de Jong
    • , Radhika Kandaswamy
    • , Peter McGuffin
    • , Niamh Mullins
    • , Margarita Rivera
    •  & Cathryn M. Lewis
  5. NIHR BRC for Mental Health, King’s College London, London, UK

    • Gerome Breen
    • , Jonathan R. I. Coleman
    • , Héléna A. Gaspar
    • , Simone de Jong
    •  & Cathryn M. Lewis
  6. Department of Biomedicine, University of Basel, Basel, Switzerland

    • Andreas J. Forstner
    • , Sascha B. Fischer
    • , Stefan Herms
    • , Per Hoffmann
    • , Thomas W. Mühleisen
    • , Céline S. Reinbold
    •  & Sven Cichon
  7. Department of Psychiatry (UPK), University of Basel, Basel, Switzerland

    • Andreas J. Forstner
  8. Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany

    • Andreas J. Forstner
    • , Franziska Degenhardt
    • , Stefan Herms
    • , Per Hoffmann
    • , Anna C. Koller
    • , Anna Maaser
    • , Markus M. Nöthen
    •  & Sven Cichon
  9. Centre for Human Genetics, University of Marburg, Marburg, Germany

    • Andreas J. Forstner
  10. Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland

    • Andreas J. Forstner
    • , Sascha B. Fischer
    • , Stefan Herms
    • , Per Hoffmann
    • , Céline S. Reinbold
    •  & Sven Cichon
  11. Division of Psychiatry, University College London, London, UK

    • Andrew McQuillin
    •  & Nicholas Bass
  12. Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA

    • Stephan Ripke
    • , Liam Abbott
    • , Richard Belliveau
    • , Felecia Cerrato
    • , Kimberly Chambert
    • , Danfeng Chen
    • , Claire Churchhouse
    • , Ashley Dumont
    • , Diane Gage
    • , Jaqueline Goldstein
    • , Phil H. Lee
    • , Steve McCarroll
    • , Mark J. Daly
    • , Benjamin M. Neale
    •  & Jordan W. Smoller
  13. Department of Psychiatry and Psychotherapy, Charité–Universitätsmedizin, Berlin, Germany

    • Stephan Ripke
    • , Vassily Trubetskoy
    •  & Swapnil Awasthi
  14. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Stephan Ripke
    • , Verneri Antilla
    • , Claire Churchhouse
    • , Phil H. Lee
    • , Mark J. Daly
    •  & Benjamin M. Neale
  15. iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark

    • Manuel Mattheisen
    • , Thomas D. Als
    • , Jakob Grove
    • , Anders D. Børglum
    •  & Preben Bo Mortensen
  16. Department of Biomedicine–Human Genetics, Aarhus University, Aarhus, Denmark

    • Manuel Mattheisen
    • , Thomas D. Als
    • , Jakob Grove
    •  & Anders D. Børglum
  17. Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden

    • Manuel Mattheisen
    •  & Ingrid Agartz
  18. Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany

    • Manuel Mattheisen
  19. iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark

    • Manuel Mattheisen
    • , Esben Agerbo
    • , Thomas D. Als
    • , Marie Bækvad-Hansen
    • , Carsten Bøcker Pedersen
    • , Jonas Bybjerg-Grauholm
    • , Marianne Giørtz Pedersen
    • , Jakob Grove
    • , Christine Søholm Hansen
    • , Anders D. Børglum
    • , David M. Hougaard
    • , Ole Mors
    • , Preben Bo Mortensen
    • , Merete Nordentoft
    •  & Thomas Werge
  20. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen, Denmark

    • Yunpeng Wang
  21. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Yunpeng Wang
  22. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    • Christiaan A. de Leeuw
    •  & Danielle Posthuma
  23. deCODE Genetics/Amgen, Reykjavik, Iceland

    • Stacy Steinberg
    • , Thorgeir E. Thorgeirsson
    • , Hreinn Stefansson
    •  & Kari Stefansson
  24. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia

    • Jennifer M. Whitehead Pavlides
    •  & Naomi R. Wray
  25. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia

    • Maciej Trzaskowski
    • , Enda M. Byrne
    • , Grant W. Montgomery
    •  & Naomi R. Wray
  26. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA

    • Tune H. Pers
  27. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, England

    • Peter A. Holmans
    • , Alexander L. Richards
    • , Valentina Escott-Price
    • , Liz Forty
    • , Christine Fraser
    • , Marian L. Hamshere
    • , Nicholas Craddock
    • , Ian Jones
    • , George Kirov
    • , Michael C. O’Donovan
    • , Michael J. Owen
    •  & Arianna Di Florio
  28. National Centre for Register-based Research and Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    •  & Preben Bo Mortensen
  29. Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA

    • Huda Akil
    •  & Fan Meng
  30. Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

    • Diego Albani
  31. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA

    • Ney Alliey-Rodriguez
    •  & Elliot S. Gershon
  32. Department of Psychiatry, Berkshire Healthcare NHS Foundation Trust, Bracknell, UK

    • Adebayo Anjorin
  33. Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA

    • Judith A. Badner
  34. 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
  35. Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA

    • Jack D. Barchas
  36. Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

    • Michael Bauer
    •  & Andrea Pfennig
  37. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Sarah E. Bergen
    • , Anders Juréus
    • , Robert Karlsson
    • , Christina M. Hultman
    • , Mikael Landén
    •  & Patrick F. Sullivan
  38. Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway

    • Erlend Bøen
    •  & Ingrid Agartz
  39. Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, the Netherlands

    • Marco P. Boks
    • , René S. Kahn
    •  & Roel A. Ophoff
  40. Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    • James Boocock
    •  & Roel A. Ophoff
  41. Institute of Psychiatric Phenomics and Genomics, University Hospital, LMU Munich, Munich, Germany

    • Monika Budde
    • , Katrin Gade
    • , Urs Heilbronner
    •  & Thomas G. Schulze
  42. Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, USA

    • William Bunney
  43. Molecular & Behavioral Neuroscience Institute and Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    • Margit Burmeister
  44. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA

    • William Byerley
  45. Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain

    • Miquel Casas
    • , Cristina Sánchez-Mora
    • , Josep Antoni Ramos-Quiroga
    •  & Marta Ribasés
  46. Department of Psychiatry, Hospital Universitari Vall d´Hebron, Barcelona, Spain

    • Miquel Casas
    • , Cristina Sánchez-Mora
    • , Josep Antoni Ramos-Quiroga
    •  & Marta Ribasés
  47. Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    • Miquel Casas
    •  & Josep Antoni Ramos-Quiroga
  48. Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addictions, Vall d´Hebron Research Institut, Universitat Autònoma de Barcelona, Barcelona, Spain

    • Miquel Casas
    • , Cristina Sánchez-Mora
    • , Josep Antoni Ramos-Quiroga
    •  & Marta Ribasés
  49. Department of Psychiatry, Mood Disorders Program, McGill University Health Center, Montreal, Quebec, Canada

    • Pablo Cervantes
    •  & Cristiana Cruceanu
  50. Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland

    • Toni-Kim Clarke
    • , Douglas H. R. Blackwood
    •  & Andrew M. McIntosh
  51. University of Iowa Hospitals and Clinics, Iowa City, IA, USA

    • William Coryell
  52. Translational Genomics, USC, Phoenix, AZ, USA

    • David W. Craig
  53. Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

    • Cristiana Cruceanu
    •  & Bertram Müller-Myhsok
  54. Centre for Psychiatry, Queen Mary University of London, London, UK

    • David Curtis
  55. UCL Genetics Institute, University College London, London, UK

    • David Curtis
  56. Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland

    • Piotr M. Czerski
    •  & Joanna Hauser
  57. Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    • Anders M. Dale
    •  & Dominic Holland
  58. Department of Radiology, University of California, San Diego, La Jolla, CA, USA

    • Anders M. Dale
  59. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    • Anders M. Dale
    • , Tiffany A. Greenwood
    • , Caroline M. Nievergelt
    • , Tatyana Shehktman
    • , Paul D. Shilling
    •  & John Kelsoe
  60. Department of Cognitive Science, University of California, San Diego, La Jolla, CA, USA

    • Anders M. Dale
    •  & Chun Chieh Fan
  61. Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium

    • Jurgen Del-Favero
  62. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • J. Raymond DePaulo
    • , Pamela B. Mahon
    • , James B. Potash
    • , Fernando Goes
    •  & Thomas G. Schulze
  63. Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo, Norway

    • Srdjan Djurovic
  64. NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway

    • Srdjan Djurovic
  65. Department of Neurology, Oslo University Hospital, Oslo, Norway

    • Torbjørn Elvsåshagen
  66. NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway

    • Torbjørn Elvsåshagen
  67. Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    • Matthew Flickinger
    • , Michael Boehnke
    •  & Laura J. Scott
  68. Department of Medical & Molecular Genetics, Indiana University, Indianapolis, IN, USA

    • Tatiana M. Foroud
  69. 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
  70. Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    • Nelson B. Freimer
    • , Loes M. Olde Loohuis
    • , Anil P. S. Ori
    •  & Roel A. Ophoff
  71. Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

    • Louise Frisén
    • , Catharina Lavebratt
    •  & Martin Schalling
  72. Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

    • Louise Frisén
    • , Lina Martinsson
    •  & Lena Backlund
  73. Child and Adolescent Psychiatry Research Center, Stockholm, Sweden

    • Louise Frisén
  74. Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany

    • Katrin Gade
    •  & Thomas G. Schulze
  75. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada

    • Julie Garnham
    • , Claire O’Donovan
    • , Claire Slaney
    •  & Martin Alda
  76. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Claudia Giambartolomei
  77. Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    • Scott D. Gordon
    • , Sarah E. Medland
    •  & Nicholas G. Martin
  78. Department of Psychological Medicine, University of Worcester, Worcester, UK

    • Katherine Gordon-Smith
    • , Amy Perry
    •  & Lisa A. Jones
  79. School of Biomedical Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth, UK

    • Elaine K. Green
  80. School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia

    • Melissa J. Green
    • , Cynthia Shannon Weickert
    • , Thomas W. Weickert
    •  & Philip B. Mitchell
  81. Neuroscience Research Australia, Sydney, New South Wales, Australia

    • Melissa J. Green
    • , Cynthia Shannon Weickert
    • , Thomas W. Weickert
    • , Janice M. Fullerton
    •  & Peter R. Schofield
  82. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    • Jakob Grove
  83. Biostatistics, University of Minnesota System, Minneapolis, MN, USA

    • Weihua Guan
  84. Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Málaga, Spain

    • José Guzman-Parra
    • , Fabio Rivas
    •  & Fermin Mayoral
  85. Department of Psychology, Eberhard Karls Universität Tübingen, Tubingen, Germany

    • Martin Hautzinger
  86. Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, USA

    • Maria Hipolito
    • , William B. Lawson
    •  & Evaristus A. Nwulia
  87. Center for Multimodal Imaging and Genetics, University of California, San Diego, La Jolla, CA, USA

    • Dominic Holland
  88. Psychiatrie Translationnelle, Inserm U955, Créteil, France

    • Stéphane Jamain
  89. Faculté de Médecine, Université Paris Est, Créteil, France

    • Stéphane Jamain
    •  & Marion Leboyer
  90. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Onatario, Canada

    • James L. Kennedy
  91. Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    • James L. Kennedy
  92. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    • James L. Kennedy
    •  & John S. Strauss
  93. Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada

    • James L. Kennedy
  94. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany

    • Sarah Kittel-Schneider
    •  & Andreas Reif
  95. Cell Biology, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA

    • James A. Knowles
  96. Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA

    • James A. Knowles
    • , Helena Medeiros
    • , Carlos Pato
    •  & Michele T. Pato
  97. ISGlobal, Barcelona, Spain

    • Manolis Kogevinas
  98. Psychiatry, Altrecht, Utrecht, the Netherlands

    • Ralph Kupka
  99. Psychiatry, GGZ inGeest, Amsterdam, the Netherlands

    • Ralph Kupka
  100. Psychiatry, VU Medisch Centrum, Amsterdam, the Netherlands

    • Ralph Kupka
  101. Department of, rth East London NHS Foundation Trust, Ilford, UK

    • Jacob Lawrence
  102. Department of Neurodegenerative Diseases and Geropsychiatry, University Hospital Bonn, Bonn, Germany

    • Markus Leber
  103. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Phil H. Lee
  104. HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA

    • Shawn E. Levy
    •  & Richard M. Myers
  105. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    • Jun Z. Li
  106. Department of Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, IL, USA

    • Chunyu Liu
  107. Max Planck Institute of Psychiatry, Munich, Germany

    • Susanne Lucae
  108. Mental Health, NHS 24, Glasgow, UK

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

    • Donald J. MacIntyre
  110. Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA

    • Pamela B. Mahon
    •  & Shaun M. Purcell
  111. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    • Wolfgang Maier
  112. Department of Genetics, Harvard Medical School, Boston, MA, USA

    • Steve McCarroll
    •  & Tõnu Esko
  113. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    • Melvin G. McInnis
    • , Fan Meng
    • , Robert C. Thompson
    • , Stanley J. Watson
    •  & Sebastian Zöllner
  114. Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France

    • James D. McKay
  115. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Lili Milani
    • , Tõnu Esko
    •  & Andres Metspalu
  116. Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland, Galway, Galway, Ireland

    • Derek W. Morris
  117. Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland

    • Derek W. Morris
    • , Aiden Corvin
    •  & Michael Gill
  118. Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany

    • Thomas W. Mühleisen
    •  & Sven Cichon
  119. Research/Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA

    • Caroline M. Nievergelt
  120. Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, Sweden

    • Annelie Nordin Adolfsson
    •  & Rolf Adolfsson
  121. Department of Clinical Psychiatry, Psychiatry Clinic, Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina

    • Lilijana Oruc
  122. Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden

    • Urban Ösby
  123. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    • Roy H. Perlis
  124. Division of Clinical Research, Massachusetts General Hospital, Boston, MA, USA

    • Roy H. Perlis
  125. Outpatient Clinic for Bipolar Disorder, Altrecht, Utrecht, the Netherlands

    • Eline J. Regeer
  126. Department of Psychiatry, Washington University in Saint Louis, Saint Louis, MO, USA

    • John P. Rice
  127. Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain

    • Margarita Rivera
  128. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Panos Roussos
  129. Medicine, Psychiatry, Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA

    • Douglas M. Ruderfer
  130. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    • Euijung Ryu
    •  & Joanna M. Biernacka
  131. Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

    • Alan F. Schatzberg
  132. Rush University Medical Center, Chicago, IL, USA

    • William A. Scheftner
  133. Scripps Translational Science Institute, La Jolla, CA, USA

    • Nicholas J. Schork
  134. Faculty of Medicine, Department of Psychiatry, School of Health Sciences, University of Iceland, Reykjavik, Iceland

    • Engilbert Sigurdsson
    •  & Kari Stefansson
  135. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Olav B. Smeland
    •  & Ole A. Andreassen
  136. NORMENT, University of Oslo, Oslo, Norway

    • Olav B. Smeland
    •  & Ole A. Andreassen
  137. Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, CA, USA

    • Janet L. Sobell
  138. Mood Disorders, PsyQ, Rotterdam, the Netherlands

    • Anne T. Spijker
  139. Institute for Medical Sciences, University of Aberdeen, Aberdeen, UK

    • David St Clair
  140. Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany

    • Michael Steffens
  141. Centre for Addiction and Mental Health, Toronto, Onatario, Canada

    • John S. Strauss
    •  & John B. Vincent
  142. Neurogenomics, TGen, Phoenix, AZ, USA

    • Szabolcs Szelinger
  143. Department of Psychiatry, Psychiatrisches Zentrum Nordbaden, Wiesloch, Germany

    • Helmut Vedder
  144. Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, USA

    • Simon Xi
  145. Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Onatario, Canada

    • Wei Xu
  146. Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    • Wei Xu
  147. Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    • Allan H. Young
  148. Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    • Peter Zandi
  149. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Peng Zhang
  150. NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine and Diakonhjemmet Hospital, University of Oslo, Oslo, Norway

    • Ingrid Agartz
  151. National Institute of Mental Health, Klecany, Czech Republic

    • Martin Alda
  152. Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia

    • Bernhard T. Baune
  153. Department of Psychiatry, University of Munster, Munster, Germany

    • Bernhard T. Baune
    •  & Udo Dannlowski
  154. Department of Psychiatry and Addiction Medicine, Assistance Publique–Hopitaux de Paris, Paris, France

    • Frank Bellivier
    • , Bruno Etain
    •  & Marion Leboyer
  155. Paris Bipolar and TRD Expert Centres, FondaMental Foundation, Paris, France

    • Frank Bellivier
  156. UMR-S1144 Team 1: Biomarkers of relapse and therapeutic response in addiction and mood disorders, INSERM, Paris, France

    • Frank Bellivier
    •  & Bruno Etain
  157. Department of Psychiatry, Université Paris Diderot, Paris, France

    • Frank Bellivier
    •  & Bruno Etain
  158. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    • Wade H. Berrettini
  159. Division of Endocrinology, Children’s Hospital Boston, Boston, MA, USA

    • Tõnu Esko
  160. Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, London, UK

    • Bruno Etain
  161. Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA

    • Mark Frye
  162. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia

    • Janice M. Fullerton
    •  & Peter R. Schofield
  163. Department of Human Genetics, University of Chicago, Chicago, IL, USA

    • Elliot S. Gershon
  164. Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania

    • Maria Grigoroiu-Serbanescu
  165. Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden

    • Mikael Landén
  166. INSERM, Paris, France

    • Marion Leboyer
  167. Department of Medical & Molecular Genetics, King’s College London, London, UK

    • Cathryn M. Lewis
  168. Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA

    • Qingqin S. Li
  169. Cancer Epidemiology and Prevention, M. Sklodowska–Curie Cancer Center and Institute of Oncology, Warsaw, Poland

    • Jolanta Lissowska
  170. School of Psychology, The University of Queensland, Brisbane, Queensland, Australia

    • Nicholas G. Martin
  171. Research Institute, Lindner Center of HOPE, Mason, OH, USA

    • Susan L. McElroy
  172. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Andrew M. McIntosh
  173. Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA

    • Francis J. McMahon
    •  & Thomas G. Schulze
  174. Division of Mental Health and Addiction and Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, Oslo, Norway

    • Ingrid Melle
  175. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia

    • Andres Metspalu
  176. Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology–NTNU, Trondheim, Norway

    • Gunnar Morken
  177. Department of Psychiatry, St Olavs University Hospital, Trondheim, Norway

    • Gunnar Morken
  178. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

    • Ole Mors
  179. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    • Bertram Müller-Myhsok
  180. University of Liverpool, Liverpool, UK

    • Bertram Müller-Myhsok
  181. Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA

    • Vishwajit Nimgaonkar
  182. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

    • Merete Nordentoft
  183. Division of Psychiatry, Haukeland Universitetssjukehus, Bergen, Norway

    • Ketil J. Oedegaard
  184. Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway

    • Ketil J. Oedegaard
  185. Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, USA

    • Sara A. Paciga
  186. College of Medicine Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA

    • Carlos Pato
  187. Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

    • Danielle Posthuma
  188. Department of Neurology and Neurosurgery, McGill University, Faculty of Medicine, Montreal, Quebec, Canada

    • Guy A. Rouleau
  189. Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada

    • Guy A. Rouleau
  190. Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy

    • Alessandro Serretti
  191. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    • Jordan W. Smoller
  192. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Jordan W. Smoller
  193. Department of Psychiatry, Hospital Namsos, Namsos, Norway

    • Eystein Stordal
  194. Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway

    • Eystein Stordal
  195. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  196. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Patrick F. Sullivan
    •  & Arianna Di Florio
  197. Department of Psychiatry, McGill University, Montreal, Quebec, Canada

    • Gustavo Turecki
  198. Department of Psychiatry, Sankt Olavs Hospital Universitetssykehuset i Trondheim, Trondheim, Norway

    • Arne E. Vaaler
  199. Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain

    • Eduard Vieta
  200. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    • Thomas Werge
  201. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Thomas Werge
  202. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA

    • John I. Nurnberger
  203. Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    • Howard J. Edenberg
  204. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Pamela Sklar

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Consortia

  1. eQTLGen Consortium

    1. BIOS Consortium

      1. the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

        Contributions

        Writing group: E.A.S., G.B., A.J.F., A. McQuillin, S.R., J.R.I.C., N.M., N.R.W., A.D.F., H.J.E., S.C., R.A.O., L.J.S., O.A.A. and J.K. PGC BD principal investigator group: E.A.S., G.B., A.J.F., A. McQuillin, D. Curtis, R.H.P., R.A., I.A., M.A., L.B., B.T.B., F.B., W.H.B., J.M.B., D.H.R.B., M. Boehnke, A.D.B., A.C., N.C., U.D., T. Esko, B.E., M. Frye, J.M.F., E.S.G., M.G., F.G., M.G.-S., J.H., D.M.H., C.M.H., I.J., L.A.J., R.S.K., M. Landén, M. Leboyer, C.M.L., Q.S.L., J. Lissowska, N.G.M., S.L.M., A.M.M., F.J.M., I.M., A. Metspalu, P.B. Mitchell, G.M., O.M., P.B. Mortensen, B.M.-M., R.M.M., B.M.N., V.N., M.N., M.M.N., M.C.O’D., K.J.O., M.J.O., S.A.P., C.P., M.T.P., J.A.R.-Q., M. Ribasés, M. Rietschel, G.A.R., M. Schalling, P.R.S., T.G.S., A.S., J.W.S., H.S., K.S., E. Stordal, G.T., A.E.V., E.V., J.B.V., T.W., J.I.N., A.D.F., H.J.E., S.C., R.A.O., L.J.S., O.A.A., J.K. and P.S. Bioinformatics: E.A.S., G.B., A.J.F., J.R.I.C., H.A.G., P.A.H., S.E.B., D.W.C., V.E.-P., C.G., M.L.H., S.H., R. Karlsson, M. Leber, C. Liu, F. Meng, L.M.O.L., A.P.S.O., C.S.R., P.R., P.D.S., M. Steffens, S. Szelinger, T.E.T., S.X., P. Zandi, eQTLGen Consortium, BIOS Consortium, T. Esko, E.S.G., Q.S.L., G.A.R. and H.S. Clinical: A. McQuillin, M.M., E.A., N.A.-R., A.A., N.B., M. Bauer, C.B.P., E.B., M.P.B., M. Budde, M. Burmeister, W. Byerley, M.C., P.C., W.C., D. Curtis, P.M.C., J.R.D., T. Elvsåshagen, L. Forty, C.F., K.G., J. Garnham, M.G.P., K.G.-S., M.J.G., J. Grove, J.G.-P., M. Hautzinger, U.H., M. Hipolito, A.J., J.L.K., S.K.-S., M.K., R. Kupka, C. Lavebratt, J. Lawrence, W.B.L., S.L., D.J.M., P.B. Mahon, W.M., L. Martinsson, P.M., M.G.M., H.M., A.N.A., E.A.N., C.O’D., L.O., U.Ö., R.H.P., A. Perry, A. Pfennig, J.B.P., E.J.R., A.R., J.P.R., F.R., M. Rivera, W.A.S., C.S.W., E. Sigurdsson, C.S., O.B.S., J.L.S., A.T.S., D.S.C., J.S.S., F.S., J.S., R.C.T., H.V., T.W.W., A.H.Y., R.A., I.A., M.A., B.T.B., F.B., D.H.R.B., A.D.B., A.C., N.C., U.D., B.E., M. Frye, E.S.G., M.G., F.G., M.G.-S., J.H., I.J., L.A.J., R.S.K., G.K., M. Landén, J. Lissowska, N.G.M., F. Mayoral, S.L.M., A.M.M., F.J.M., I.M., P.B. Mitchell, G.M., O.M., P.B. Mortensen, V.N., M.C.O’D., K.J.O., M.J.O., C.P., M.T.P., J.A.R.-Q., M. Rietschel, T.G.S., A.S., J.W.S., E. Stordal, A.E.V., E.V., J.I.N. and A.D.F. Genomic assays/data generation: G.B., A.J.F., E.A., D.A., M.B.-H., C.B.P., J.B.-G., T.-K.C., D.W.C., C. Cruceanu, F.D., J.D.-F., S.D., S.B.F., J.F., M.G.P., E.K.G., P.H., S.J., R. Kandaswamy, A.C.K., S.E.L., A. Maaser, J.D.M., L. Milani, G.W.M., D.W.M., T.W.M., E.R., C.S.-M., T.S., C.S.H., S. Szelinger, J.T., S.H.W., P. Zhang, A.C., T. Esko, J.M.F., E.S.G., M.G., D.M.H., R.M.M., M.M.N., M. Ribasés, G.A.R., G.T. and S.C. Obtained funding for BD samples: G.B., H.A., N.A.-R., J.D.B., W. Bunney, J.R.D., N.B.F., L. Frisén, M.J.G., S.J., J.A.K., C. Lavebratt, S.L., P.M., G.W.M., U.Ö., J.B.P., M. Rivera, A.F.S., C.S.W., S.J.W., T.W.W., A.H.Y., M.A., B.T.B., W.H.B., J.M.B., M.Boehnke, A.D.B., A.C., N.C., M. Frye, J.M.F., E.S.G., M.G., M.G.-S., I.J., L.A.J., M. Landén, M. Leboyer, C.M.L., N.G.M., A. Metspalu, P.B. Mitchell, O.M., P.B. Mortensen, B.M.N., M.N., M.M.N., M.C.O’D., M.J.O., C.P., M.T.P., M. Rietschel, G.A.R., P.R.S., T.G.S., J.W.S., G.T., J.B.V., T.W., J.I.N., H.J.E., R.A.O. and P.S. Statistical analysis: E.A.S., G.B., S.R., V.T., M.M., Y.W., J.R.I.C., H.A.G., C.A.d.L., S. Steinberg, J.M.W.P., M.T., E.M.B., T.H.P., P.A.H., A.L.R., L.A., N.A.-R., T.D.A., V.A., S.A., J.A.B., R.B., S.E.B., J.B., F.C., K.C., A.W.C., D. Chen, C. Churchhouse, A.M.D., S.d.J., A.L.D., A.D., V.E.-P., C.C.F., M. Flickinger, T.M.F., D.G., C.G., J. Goldstein, S.D.G., T.A.G., J. Grove, W.G., M.L.H., D.H., L.H., J.S.J., R. Karlsson, M. Leber, P.H.L., J.Z.L., S.M., S.E.M., D.W.M., N.M., H.N., C.M.N., L.M.O.L., A.P.S.O., S.M.P., C.S.R., P.R., D.M.R., N.J.S., O.B.S., T.E.T., W.W., W.X., P. Zandi, P. Zhang, S.Z., eQTLGen Consortium, BIOS Consortium, J.M.B., A.D.B., M.J.D., E.S.G., F.G., Q.S.L., B.M.-M., D.P., H.S., P.F.S., N.R.W. and P.S.

        Competing interests

        T.E.T., S. Steinberg, H.S. and K.S. are employed by deCODE Genetics/Amgen. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and is on advisory boards for the following companies with drugs used in affective and related disorders: Astra Zeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, Livanova. A.H.Y. is Lead Investigator for Embolden Study (Astra Zeneca), BCI Neuroplasticity Study and Aripiprazole Mania Study, which are investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. J.N. is an investigator for Janssen. P.F.S. reports the following potentially competing interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member) and Roche (grant recipient, speaker reimbursement). G.B. reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. O.A.A. has received speaker fees from Lundbeck. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab and Rubió in the last 5 years. He also received travel awards (air tickets and hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire and Eli Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious and Rubió. E.V. has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Astra Zeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. T. Elvsåshagen has received speaker fees from Lundbeck. All other authors declare no competing interests.

        Corresponding authors

        Correspondence to Eli A. Stahl or John Kelsoe.

        Supplementary information

        1. Supplementary Information

          Supplementary Figs. 1–7 and Supplementary Notes

        2. Reporting Summary

        3. Supplementary Tables

          Supplementary Tables 1–18

        4. Supplementary Data 1

          Regional association plots for all 31 lead SNPs in the 30 genome-wide-significant loci.

        5. Supplementary Data 2

          Forest plots of the 32 primary GWAS datasets for all 31 lead SNPs in the 30 genome-wide-significant loci.

        6. Supplementary Data 3

          Forest plots of the 7 follow-up datasets for all 31 lead SNPs in the 30 genome-wide-significant loci.

        About this article

        Publication history

        Received

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        Issue Date

        DOI

        https://doi.org/10.1038/s41588-019-0397-8

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