Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology,Nature Genetics

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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
Nature Genetics ( IF 31.7 ) Pub Date : 2021-05-17 , DOI: 10.1038/s41588-021-00857-4
Niamh Mullins _{1,

2} , Andreas J Forstner _{3,

4,

5} , Kevin S O'Connell _{6,

7} , Brandon Coombes ₈ , Jonathan R I Coleman _{9,

10} , Zhen Qiao ₁₁ , Thomas D Als _{12,

13,

14} , Tim B Bigdeli _{15,

16} , Sigrid Børte _{17,

18,

19} , Julien Bryois ₂₀ , Alexander W Charney ₂ , Ole Kristian Drange _{21,

22} , Michael J Gandal ₂₃ , Saskia P Hagenaars _{9,

10} , Masashi Ikeda ₂₄ , Nolan Kamitaki _{25,

26} , Minsoo Kim ₂₃ , Kristi Krebs ₂₇ , Georgia Panagiotaropoulou ₂₈ , Brian M Schilder _{1,

29,

30,

31} , Laura G Sloofman ₁ , Stacy Steinberg ₃₂ , Vassily Trubetskoy ₂₈ , Bendik S Winsvold _{19,

33} , Hong-Hee Won ₃₄ , Liliya Abramova ₃₅ , Kristina Adorjan _{36,

37} , Esben Agerbo _{14,

38,

39} , Mariam Al Eissa ₄₀ , Diego Albani ₄₁ , Ney Alliey-Rodriguez _{42,

43} , Adebayo Anjorin ₄₄ , Verneri Antilla ₄₅ , Anastasia Antoniou ₄₆ , Swapnil Awasthi ₂₈ , Ji Hyun Baek ₄₇ , Marie Bækvad-Hansen _{14,

48} , Nicholas Bass ₄₀ , Michael Bauer ₄₉ , Eva C Beins ₃ , Sarah E Bergen ₂₀ , Armin Birner ₅₀ , Carsten Bøcker Pedersen _{14,

38,

39} , Erlend Bøen ₅₁ , Marco P Boks ₅₂ , Rosa Bosch _{53,

54,

55,

56} , Murielle Brum ₅₇ , Ben M Brumpton ₁₉ , Nathalie Brunkhorst-Kanaan ₅₇ , Monika Budde ₃₆ , Jonas Bybjerg-Grauholm _{14,

48} , William Byerley ₅₈ , Murray Cairns ₅₉ , Miquel Casas _{53,

54,

55,

56} , Pablo Cervantes ₆₀ , Toni-Kim Clarke ₆₁ , Cristiana Cruceanu _{60,

62} , Alfredo Cuellar-Barboza _{63,

64} , Julie Cunningham ₆₅ , David Curtis _{66,

67} , Piotr M Czerski ₆₈ , Anders M Dale ₆₉ , Nina Dalkner ₅₀ , Friederike S David ₃ , Franziska Degenhardt _{3,

70} , Srdjan Djurovic _{71,

72} , Amanda L Dobbyn _{1,

2} , Athanassios Douzenis ₄₆ , Torbjørn Elvsåshagen _{18,

73,

74} , Valentina Escott-Price ₇₅ , I Nicol Ferrier ₇₆ , Alessia Fiorentino ₄₀ , Tatiana M Foroud ₇₇ , Liz Forty ₇₅ , Josef Frank ₇₈ , Oleksandr Frei _{6,

18} , Nelson B Freimer _{23,

79} , Louise Frisén ₈₀ , Katrin Gade _{36,

81} , Julie Garnham ₈₂ , Joel Gelernter _{83,

84,

85} , Marianne Giørtz Pedersen _{14,

38,

39} , Ian R Gizer ₈₆ , Scott D Gordon ₈₇ , Katherine Gordon-Smith ₈₈ , Tiffany A Greenwood ₈₉ , Jakob Grove _{12,

13,

14,

90} , José Guzman-Parra ₉₁ , Kyooseob Ha ₉₂ , Magnus Haraldsson ₉₃ , Martin Hautzinger ₉₄ , Urs Heilbronner ₃₆ , Dennis Hellgren ₂₀ , Stefan Herms _{3,

95,

96} , Per Hoffmann _{3,

95,

96} , Peter A Holmans ₇₅ , Laura Huckins _{1,

2} , Stéphane Jamain _{97,

98} , Jessica S Johnson _{1,

2} , Janos L Kalman _{36,

37,

99} , Yoichiro Kamatani _{100,

101} , James L Kennedy _{102,

103,

104,

105} , Sarah Kittel-Schneider _{57,

106} , James A Knowles _{107,

108} , Manolis Kogevinas ₁₀₉ , Maria Koromina ₁₁₀ , Thorsten M Kranz ₅₇ , Henry R Kranzler _{111,

112} , Michiaki Kubo ₁₁₃ , Ralph Kupka _{114,

115,

116} , Steven A Kushner ₁₁₇ , Catharina Lavebratt _{118,

119} , Jacob Lawrence ₁₂₀ , Markus Leber ₁₂₁ , Heon-Jeong Lee ₁₂₂ , Phil H Lee ₁₂₃ , Shawn E Levy ₁₂₄ , Catrin Lewis ₇₅ , Calwing Liao _{125,

126} , Susanne Lucae ₆₂ , Martin Lundberg _{118,

119} , Donald J MacIntyre ₁₂₇ , Sigurdur H Magnusson ₃₂ , Wolfgang Maier ₁₂₈ , Adam Maihofer ₈₉ , Dolores Malaspina _{1,

2} , Eirini Maratou ₁₂₉ , Lina Martinsson ₈₀ , Manuel Mattheisen _{12,

13,

14,

106,

130} , Steven A McCarroll _{25,

26} , Nathaniel W McGregor ₁₃₁ , Peter McGuffin ₉ , James D McKay ₁₃₂ , Helena Medeiros ₁₀₈ , Sarah E Medland ₈₇ , Vincent Millischer _{118,

119} , Grant W Montgomery ₁₁ , Jennifer L Moran _{25,

133} , Derek W Morris ₁₃₄ , Thomas W Mühleisen _{4,

95} , Niamh O'Brien ₄₀ , Claire O'Donovan ₈₂ , Loes M Olde Loohuis _{23,

79} , Lilijana Oruc ₁₃₅ , Sergi Papiol _{36,

37} , Antonio F Pardiñas ₇₅ , Amy Perry ₈₈ , Andrea Pfennig ₄₉ , Evgenia Porichi ₄₆ , James B Potash ₁₃₆ , Digby Quested _{137,

138} , Towfique Raj _{1,

29,

30,

31} , Mark H Rapaport ₁₃₉ , J Raymond DePaulo ₁₃₆ , Eline J Regeer ₁₄₀ , John P Rice ₁₄₁ , Fabio Rivas ₉₁ , Margarita Rivera _{142,

143} , Julian Roth ₁₀₆ , Panos Roussos _{1,

2,

29} , Douglas M Ruderfer ₁₄₄ , Cristina Sánchez-Mora _{53,

54,

56,

145} , Eva C Schulte _{36,

37} , Fanny Senner _{36,

37} , Sally Sharp ₄₀ , Paul D Shilling ₈₉ , Engilbert Sigurdsson _{93,

146} , Lea Sirignano ₇₈ , Claire Slaney ₈₂ , Olav B Smeland _{6,

7} , Daniel J Smith ₁₄₇ , Janet L Sobell ₁₄₈ , Christine Søholm Hansen _{14,

48} , Maria Soler Artigas _{53,

54,

56,

145} , Anne T Spijker ₁₄₉ , Dan J Stein ₁₅₀ , John S Strauss ₁₀₂ , Beata Świątkowska ₁₅₁ , Chikashi Terao ₁₀₁ , Thorgeir E Thorgeirsson ₃₂ , Claudio Toma _{152,

153,

154} , Paul Tooney ₅₉ , Evangelia-Eirini Tsermpini ₁₁₀ , Marquis P Vawter ₁₅₅ , Helmut Vedder ₁₅₆ , James T R Walters ₇₅ , Stephanie H Witt ₇₈ , Simon Xi ₁₅₇ , Wei Xu ₁₅₈ , Jessica Mei Kay Yang ₇₅ , Allan H Young _{159,

160} , Hannah Young ₁ , Peter P Zandi ₁₃₆ , Hang Zhou _{83,

84} , Lea Zillich ₇₈ , , Rolf Adolfsson ₁₆₁ , Ingrid Agartz _{51,

130,

162} , Martin Alda _{82,

163} , Lars Alfredsson ₁₆₄ , Gulja Babadjanova ₁₆₅ , Lena Backlund _{118,

119} , Bernhard T Baune _{166,

167,

168} , Frank Bellivier _{169,

170} , Susanne Bengesser ₅₀ , Wade H Berrettini ₁₇₁ , Douglas H R Blackwood ₆₁ , Michael Boehnke ₁₇₂ , Anders D Børglum _{14,

173,

174} , Gerome Breen _{9,

10} , Vaughan J Carr ₁₇₅ , Stanley Catts ₁₇₆ , Aiden Corvin ₁₇₇ , Nicholas Craddock ₇₅ , Udo Dannlowski ₁₆₆ , Dimitris Dikeos ₁₇₈ , Tõnu Esko _{26,

27,

179,

180} , Bruno Etain _{169,

170} , Panagiotis Ferentinos _{9,

46} , Mark Frye ₆₄ , Janice M Fullerton _{152,

153} , Micha Gawlik ₁₀₆ , Elliot S Gershon _{42,

181} , Fernando S Goes ₁₃₆ , Melissa J Green _{152,

175} , Maria Grigoroiu-Serbanescu ₁₈₂ , Joanna Hauser ₆₈ , Frans Henskens ₅₉ , Jan Hillert ₈₀ , Kyung Sue Hong ₄₇ , David M Hougaard _{14,

48} , Christina M Hultman ₂₀ , Kristian Hveem _{19,

183} , Nakao Iwata ₂₄ , Assen V Jablensky ₁₈₄ , Ian Jones ₇₅ , Lisa A Jones ₈₈ , René S Kahn _{2,

52} , John R Kelsoe ₈₉ , George Kirov ₇₅ , Mikael Landén _{20,

185} , Marion Leboyer _{97,

98,

186} , Cathryn M Lewis _{9,

10,

187} , Qingqin S Li ₁₈₈ , Jolanta Lissowska ₁₈₉ , Christine Lochner ₁₉₀ , Carmel Loughland ₅₉ , Nicholas G Martin _{87,

191} , Carol A Mathews ₁₉₂ , Fermin Mayoral ₉₁ , Susan L McElroy ₁₉₃ , Andrew M McIntosh _{127,

194} , Francis J McMahon ₁₉₅ , Ingrid Melle _{6,

196} , Patricia Michie ₅₉ , Lili Milani ₂₇ , Philip B Mitchell ₁₇₅ , Gunnar Morken _{21,

197} , Ole Mors _{14,

198} , Preben Bo Mortensen _{12,

14,

38,

39} , Bryan Mowry ₁₇₆ , Bertram Müller-Myhsok _{62,

199,

200} , Richard M Myers ₁₂₄ , Benjamin M Neale _{25,

45,

179} , Caroline M Nievergelt _{89,

201} , Merete Nordentoft _{14,

202} , Markus M Nöthen ₃ , Michael C O'Donovan ₇₅ , Ketil J Oedegaard _{203,

204} , Tomas Olsson ₂₀₅ , Michael J Owen ₇₅ , Sara A Paciga ₂₀₆ , Chris Pantelis ₂₀₇ , Carlos Pato ₁₀₈ , Michele T Pato ₁₀₈ , George P Patrinos _{110,

208,

209} , Roy H Perlis _{210,

211} , Danielle Posthuma _{212,

213} , Josep Antoni Ramos-Quiroga _{53,

54,

55,

56} , Andreas Reif ₅₇ , Eva Z Reininghaus ₅₀ , Marta Ribasés _{53,

54,

56,

145} , Marcella Rietschel ₇₈ , Stephan Ripke _{25,

28,

45} , Guy A Rouleau _{126,

214} , Takeo Saito ₂₄ , Ulrich Schall ₅₉ , Martin Schalling _{118,

119} , Peter R Schofield _{152,

153} , Thomas G Schulze _{36,

78,

81,

136,

215} , Laura J Scott ₁₇₂ , Rodney J Scott ₅₉ , Alessandro Serretti ₂₁₆ , Cynthia Shannon Weickert _{152,

175,

217} , Jordan W Smoller _{25,

133,

218} , Hreinn Stefansson ₃₂ , Kari Stefansson _{32,

219} , Eystein Stordal _{220,

221} , Fabian Streit ₇₈ , Patrick F Sullivan _{20,

222,

223} , Gustavo Turecki ₂₂₄ , Arne E Vaaler ₂₂₅ , Eduard Vieta ₂₂₆ , John B Vincent ₁₀₂ , Irwin D Waldman ₂₂₇ , Thomas W Weickert _{152,

175,

217} , Thomas Werge _{14,

228,

229,

230} , Naomi R Wray _{11,

231} , John-Anker Zwart _{18,

19,

33} , Joanna M Biernacka _{8,

64} , John I Nurnberger ₂₃₂ , Sven Cichon _{3,

4,

95,

96} , Howard J Edenberg _{77,

233} , Eli A Stahl _{1,

2,

179} , Andrew McQuillin ₄₀ , Arianna Di Florio _{75,

223} , Roel A Ophoff _{23,

79,

117,

234} , Ole A Andreassen _{6,

7}

Affiliation

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
Centre for Human Genetics, University of Marburg, Marburg, Germany.
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
NORMENT, University of Oslo, Oslo, Norway.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
NIHR Maudsley BRC, King's College London, London, UK.
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
VA NY Harbor Healthcare System, Brooklyn, NY, USA.
Research and Communication Unit for Musculoskeletal Health, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
K. G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Department of Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Department of Østmarka, Division of Mental Health Care, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Department of Psychiatry and Biobehavioral Science, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry, School of Medicine, Fujita Health University, Toyoake, Japan.
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
deCODE Genetics/Amgen, Reykjavik, Iceland.
Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea.
Russian Academy of Medical Sciences, Mental Health Research Center, Moscow, Russian Federation.
Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Centre for Integrated Register-Based Research, Aarhus University, Aarhus, Denmark.
Division of Psychiatry, University College London, London, UK.
Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA.
Northwestern University, Chicago, IL, USA.
Psychiatry, Berkshire Healthcare NHS Foundation Trust, Bracknell, UK.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
2nd Department of Psychiatry, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Department of Psychiatry, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul, South Korea.
Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria.
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway.
Psychiatry, Brain Center UMC Utrecht, Utrecht, the Netherlands.
Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, Spain.
Department of Psychiatry, Hospital Universitari Vall d´Hebron, Barcelona, Spain.
Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain.
Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addictions, Vall d´Hebron Research Institut (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
Psychiatry, University of California San Francisco, San Francisco, CA, USA.
University of Newcastle, Newcastle, New South Wales, Australia.
Mood Disorders Program, Department of Psychiatry, McGill University Health Center, Montreal, Quebec, Canada.
Division of Psychiatry, University of Edinburgh, Edinburgh, UK.
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Department of Psychiatry, Universidad Autonoma de Nuevo Leon, Monterrey, Mexico.
Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Centre for Psychiatry, Queen Mary University of London, London, UK.
UCL Genetics Institute, University College London, London, UK.
Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland.
Center for Multimodal Imaging and Genetics, Departments of Neurosciences, Radiology, and Psychiatry, University of California, San Diego, CA, USA.
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany.
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
Department of Neurology, Oslo University Hospital, Oslo, Norway.
NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway.
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Academic Psychiatry, Newcastle University, Newcastle upon Tyne, UK.
Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA.
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA.
Departments of Genetics and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
Department of Psychological Sciences, University of Missouri, Columbia, MO, USA.
Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Psychological Medicine, University of Worcester, Worcester, UK.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Málaga, Spain.
Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea.
Landspitali University Hospital, Reykjavik, Iceland.
Department of Psychology, Eberhard Karls Universität Tübingen, Tübingen, Germany.
Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
Neuropsychiatrie Translationnelle, Inserm U955, Créteil, France.
Faculté de Santé, Université Paris Est, Créteil, France.
International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany.
Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada.
Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.
Cell Biology, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA.
Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, USA.
ISGlobal, Barcelona, Spain.
Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.
Mental Illness Research, Education and Clinical Center, Crescenz VAMC, Philadelphia, PA, USA.
Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Psychiatry, Altrecht, Utrecht, the Netherlands.
Psychiatry, GGZ inGeest, Amsterdam, the Netherlands.
Psychiatry, VU Medisch Centrum, Amsterdam, the Netherlands.
Department of Psychiatry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
Psychiatry, North East London NHS Foundation Trust, Ilford, UK.
Clinic for Psychiatry and Psychotherapy, University Hospital Cologne, Cologne, Germany.
Department of Psychiatry, Korea University College of Medicine, Seoul, South Korea.
Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada.
Division of Psychiatry, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
Clinical Biochemistry Laboratory, Attikon General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, Sweden.
Systems Genetics Working Group, Department of Genetics, Stellenbosch University, Stellenbosch, South Africa.
Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, France.
Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Centre for Neuroimaging and Cognitive Genomics (NICOG), National University of Ireland Galway, Galway, Ireland.
Medical Faculty, School of Science and Technology, University Sarajevo, Sarajevo, Bosnia and Herzegovina.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA.
Outpatient Clinic for Bipolar Disorder, Altrecht, Utrecht, the Netherlands.
Department of Psychiatry, Washington University in Saint Louis, Saint Louis, MO, USA.
Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
Institute of Neurosciences, Biomedical Research Center (CIBM), University of Granada, Granada, Spain.
Medicine, Psychiatry, Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
Faculty of Medicine, Department of Psychiatry, School of Health Sciences, University of Iceland, Reykjavik, Iceland.
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, CA, USA.
Mood Disorders, PsyQ, Rotterdam, the Netherlands.
SAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
Neuroscience Research Australia, Sydney, New South Wales, Australia.
School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid and CSIC, Madrid, Spain.
Department of Psychiatry and Human Behavior, School of Medicine, University of California, Irvine, Irvine, CA, USA.
Psychiatry, Psychiatrisches Zentrum Nordbaden, Wiesloch, Germany.
Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, USA.
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, UK.
Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, Sweden.
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.
National Institute of Mental Health, Klecany, Czech Republic.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Institute of Pulmonology, Russian State Medical University, Moscow, Russian Federation.
Department of Psychiatry, University of Münster, Münster, Germany.
Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Université de Paris, INSERM, Optimisation Thérapeutique en Neuropsychopharmacologie, UMRS 1144, Paris, France.
APHP Nord, DMU Neurosciences, Département de Psychiatrie et de Médecine Addictologique, GHU Saint Louis-Lariboisière-Fernand Widal, Paris, France.
Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Department of Biomedicine and the iSEQ Center, Aarhus University, Aarhus, Denmark.
Center for Genomics and Personalized Medicine, CGPM, Aarhus, Denmark.
School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia.
University of Queensland, Brisbane, Queensland, Australia.
Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
1st Department of Psychiatry, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Division of Endocrinology, Children's Hospital Boston, Boston, MA, USA.
Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
HUNT Research Center, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
University of Western Australia, Nedlands, Western Australia, Australia.
Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Department of Psychiatry and Addiction Medicine, Assistance Publique - Hôpitaux de Paris, Paris, France.
Department of Medical and Molecular Genetics, King's College London, London, UK.
Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, USA.
Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
SA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa.
School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
Department of Psychiatry and Genetics Institute, University of Florida, Gainesville, FL, USA.
Research Institute, Lindner Center of HOPE, Mason, OH, USA.
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA.
Division of Mental Health and Addiction, University of Oslo, Institute of Clinical Medicine, Oslo, Norway.
Psychiatry, St Olavs University Hospital, Trondheim, Norway.
Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Risskov, Denmark.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
University of Liverpool, Liverpool, UK.
Research/Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
Division of Psychiatry, Haukeland Universitetssjukehus, Bergen, Norway.
Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
Department of Clinical Neuroscience and Center for Molecular Medicine, Karolinska Institutet at Karolinska University Hospital, Solna, Sweden.
Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, USA.
University of Melbourne, Melbourne, Victoria, Australia.
Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
Zayed Center of Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
Psychiatry, Harvard Medical School, Boston, MA, USA.
Division of Clinical Research, Massachusetts General Hospital, Boston, MA, USA.
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy.
Department of Neuroscience, SUNY Upstate Medical University, Syracuse, NY, USA.
Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Department of Psychiatry, Hospital Namsos, Namsos, Norway.
Department of Neuroscience, Norges Teknisk Naturvitenskapelige Universitet Fakultet for Naturvitenskap og Teknologi, Trondheim, Norway.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
Department of Psychiatry, Sankt Olavs Hospital Universitetssykehuset i Trondheim, Trondheim, Norway.
Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
Department of Psychology, Emory University, Atlanta, GA, USA.
Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Center for GeoGenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark.
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

中文翻译：

对 40,000 多个双相情感障碍病例进行的全基因组关联研究为潜在生物学提供了新的见解

双相情感障碍是一种病因复杂的遗传性精神疾病。我们对 41,917 名双相情感障碍病例和 371,549 名欧洲血统对照进行了全基因组关联研究，确定了 64 个相关基因组位点。双相情感障碍风险等位基因在突触信号通路和大脑表达基因中富集，特别是在前额皮质和海马神经元中具有高特异性表达的基因。在编码抗精神病药、钙通道阻滞剂、抗癫痫药和麻醉药靶标的基因中发现了显着的信号富集。整合表达数量性状基因座数据表明，15 个基因通过基因表达与双相情感障碍密切相关，编码 HTR6、MCHR1、DCLK3 和 FURIN 等可药物靶标。对双相情感障碍亚型的分析表明，双相情感障碍 I 型和 II 型之间存在高度但不完善的遗传相关性，并确定了其他相关位点。总之，这些结果增进了我们对双相情感障碍的生物学病因学的理解，确定了新的治疗线索，并优先考虑基因进行功能性后续研究。

更新日期：2021-05-17

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