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.

1st Department of Psychiatry Eginition Hospital National and Kapodistrian University of Athens Athens Greece

2nd Department of Psychiatry Attikon General Hospital National and Kapodistrian University of Athens Athens Greece

Academic Psychiatry Newcastle University Newcastle upon Tyne UK

Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA USA

APHP Nord DMU Neurosciences Département de Psychiatrie et de Médecine Addictologique GHU Saint Louis Lariboisière Fernand Widal Paris France

Biochemistry and Molecular Biology Indiana University School of Medicine Indianapolis IN USA

Bioinformatics Research Centre Aarhus University Aarhus Denmark

Biometric Psychiatric Genetics Research Unit Alexandru Obregia Clinical Psychiatric Hospital Bucharest Romania

Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health Toronto Ontario Canada

Cancer Epidemiology and Prevention M Sklodowska Curie National Research Institute of Oncology Warsaw Poland

Cell Biology SUNY Downstate Medical Center College of Medicine Brooklyn NY USA

Center for Genomics and Personalized Medicine CGPM Aarhus Denmark

Center for GeoGenetics GLOBE Institute University of Copenhagen Copenhagen Denmark

Center for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Center for Multimodal Imaging and Genetics Departments of Neurosciences Radiology and Psychiatry University of California San Diego CA USA

Center for Neonatal Screening Department for Congenital Disorders Statens Serum Institut Copenhagen Denmark

Center for Neurobehavioral Genetics Semel Institute for Neuroscience and Human Behavior Los Angeles CA USA

Center for Statistical Genetics and Department of Biostatistics University of Michigan Ann Arbor MI USA

Center for Studies of Addiction University of Pennsylvania Perelman School of Medicine Philadelphia PA USA

Centre for Cognitive Ageing and Cognitive Epidemiology University of Edinburgh Edinburgh UK

Centre for Human Genetics University of Marburg Marburg Germany

Centre for Integrated Register Based Research Aarhus University Aarhus Denmark

Centre for Neuroimaging and Cognitive Genomics National University of Ireland Galway Galway Ireland

Centre for Psychiatry Queen Mary University of London London UK

Centro de Biología Molecular Severo Ochoa Universidad Autónoma de Madrid and CSIC Madrid Spain

Clinic for Psychiatry and Psychotherapy University Hospital Cologne Cologne Germany

Clinical Biochemistry Laboratory Attikon General Hospital Medical School National and Kapodistrian University of Athens Athens Greece

Clinical Institute of Neuroscience Hospital Clinic University of Barcelona IDIBAPS CIBERSAM Barcelona Spain

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 Biochemistry and Molecular Biology 2 Faculty of Pharmacy University of Granada Granada Spain

Department of Biomedical and NeuroMotor Sciences University of Bologna Bologna Italy

Department of Biomedicine and the iSEQ Center Aarhus University Aarhus Denmark

Department of Biomedicine Human Genetics Aarhus University Aarhus Denmark

Department of Biomedicine University of Basel Basel Switzerland

Department of Child and Adolescent Psychiatry Psychosomatics and Psychotherapy University Hospital Essen University of Duisburg Essen Duisburg Germany

Department of Clinical Genetics Amsterdam Neuroscience Vrije Universiteit Medical Center Amsterdam the Netherlands

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Neuroscience and Center for Molecular Medicine Karolinska Institutet at Karolinska University Hospital Solna Sweden

Department of Clinical Neuroscience Centre for Psychiatry Research Karolinska Institutet Stockholm Sweden

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Clinical Sciences Psychiatry Umeå University Medical Faculty Umeå Sweden

Department of Complex Trait Genetics Center for Neurogenomics and Cognitive Research Amsterdam Neuroscience Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Lodz Poland

Department of Genetic Epidemiology in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

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

Department of Genetics Harvard Medical School Boston MA USA

Department of Genetics Microbiology and Statistics Faculty of Biology Universitat de Barcelona Barcelona Spain

Department of Genetics University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Health Sciences Research Mayo Clinic Rochester MN USA

Department of Human Genetics David Geffen School of Medicine University of California Los Angeles Los Angeles CA USA

Department of Human Genetics McGill University Montréal Quebec Canada

Department of Human Genetics University of Chicago Chicago IL USA

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Medical and Molecular Genetics Indiana University Indianapolis IN USA

Department of Medical and Molecular Genetics King's College London London UK

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medical Genetics Oslo University Hospital Oslo Norway

Department of Mental Health Faculty of Medicine and Health Sciences Norwegian University of Science and Technology Trondheim Norway

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Neurology and Neurosurgery Faculty of Medicine McGill University Montreal Quebec Canada

Department of Neurology Oslo University Hospital Oslo Norway

Department of Neuroscience Icahn School of Medicine at Mount Sinai New York NY USA

Department of Neuroscience Istituto Di Ricerche Farmacologiche Mario Negri IRCCS Milan Italy

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Department of Neuroscience SUNY Upstate Medical University Syracuse NY USA

Department of Østmarka Division of Mental Health Care St Olavs Hospital Trondheim University Hospital Trondheim Norway

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Department of Psychiatric Research Diakonhjemmet Hospital Oslo Norway

Department of Psychiatry and Addiction Medicine Assistance Publique Hôpitaux de Paris Paris France

Department of Psychiatry and Behavioral Neuroscience University of Chicago Chicago IL USA

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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 and Forensic Medicine Universitat Autònoma de Barcelona Barcelona Spain

Department of Psychiatry and Genetics Institute University of Florida Gainesville FL USA

Department of Psychiatry and Human Behavior School of Medicine University of California Irvine Irvine CA USA

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Department of Psychiatry and Psychotherapeutic Medicine Medical University of Graz Graz Austria

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Germany

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Department of Psychiatry and Psychotherapy University Hospital LMU Munich Munich Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Department of Psychiatry and Psychotherapy University of Bonn Bonn Germany

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Department of Psychiatry Erasmus MC University Medical Center Rotterdam Rotterdam the Netherlands

Department of Psychiatry Hospital Namsos Namsos Norway

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Department of Psychiatry Icahn School of Medicine at Mount Sinai New York NY USA

Department of Psychiatry Korea University College of Medicine Seoul South Korea

Department of Psychiatry Laboratory of Psychiatric Genetics Poznan University of Medical Sciences Poznan Poland

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Department of Psychiatry Melbourne Medical School The University of Melbourne Melbourne Victoria Australia

Department of Psychiatry Psychosomatic Medicine and Psychotherapy University Hospital Frankfurt Frankfurt am Main Germany

Department of Psychiatry Psychosomatics and Psychotherapy Center of Mental Health University Hospital Würzburg Würzburg Germany

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eCODE Genetics Amgen Reykjavik Iceland

Estelle and Daniel Maggin Department of Neurology Icahn School of Medicine at Mount Sinai New York NY USA

Estonian Genome Center Institute of Genomics University of Tartu Tartu Estonia

Faculté de Santé Université Paris Est Créteil France

Faculty of Medicine and Dentistry University of Bergen Bergen Norway

Faculty of Medicine Department of Psychiatry School of Health Sciences University of Iceland Reykjavik Iceland

Faculty of Medicine University of Iceland Reykjavik Iceland

Genetic Cancer Susceptibility Group International Agency for Research on Cancer Lyon France

Genetics and Computational Biology QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

HudsonAlpha Institute for Biotechnology Huntsville AL USA

Human Genetics and Computational Biomedicine Pfizer Global Research and Development Groton CT USA

Human Genetics Branch Intramural Research Program National Institute of Mental Health Bethesda MD USA

HUNT Research Center Department of Public Health and Nursing Faculty of Medicine and Health Sciences Norwegian University of Science and Technology Trondheim Norway

Institute for Genomic Health SUNY Downstate Medical Center College of Medicine Brooklyn NY USA

Institute for Molecular Bioscience The University of Queensland Brisbane Queensland Australia

Institute of Biological Psychiatry Mental Health Services Copenhagen University Hospital Copenhagen Denmark

Institute of Clinical Medicine University of Oslo Oslo Norway

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Health and Wellbeing University of Glasgow Glasgow UK

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Institute of Medical Sciences University of Toronto Toronto Ontario Canada

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Institute of Neurosciences Biomedical Research Center University of Granada Granada Spain

Institute of Psychiatric Phenomics and Genomics University Hospital LMU Munich Munich Germany

Institute of Pulmonology Russian State Medical University Moscow Russian Federation

Instituto de Salud Carlos 3 Biomedical Network Research Centre on Mental Health Madrid Spain

International Max Planck Research School for Translational Psychiatry Munich Germany

iPSYCH The Lundbeck Foundation Initiative for Integrative Psychiatric Research Aarhus Denmark

iSEQ Center for Integrative Sequencing Aarhus University Aarhus Denmark

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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

Laboratory for Statistical and Translational Genetics RIKEN Center for Integrative Medical Sciences Yokohama Japan

Laboratory of Complex Trait Genomics Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences The University of Tokyo Tokyo Japan

Laboratory of Pharmacogenomics and Individualized Therapy Department of Pharmacy School of Health Sciences University of Patras Patras Greece

Landspitali University Hospital Reykjavik Iceland

Medical and Population Genetics Broad Institute Cambridge MA USA

Medical Faculty School of Science and Technology University Sarajevo Sarajevo Bosnia and Herzegovina

Medical Research Council Centre for Neuropsychiatric Genetics and Genomics Division of Psychological Medicine and Clinical Neurosciences Cardiff University Cardiff UK

Medicine Psychiatry Biomedical Informatics Vanderbilt University Medical Center Nashville TN USA

Mental Health Department University Regional Hospital Biomedicine Institute Málaga Spain

Mental Health Services in the Capital Region of Denmark Mental Health Center Copenhagen University of Copenhagen Copenhagen Denmark

Mental Illness Research Education and Clinical Center Crescenz VAMC Philadelphia PA USA

Montreal Neurological Institute and Hospital McGill University Montréal Quebec Canada

Mood Disorders Program Department of Psychiatry McGill University Health Center Montreal Quebec Canada

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NORMENT University of Oslo Oslo Norway

Northwestern University Chicago IL USA

Outpatient Clinic for Bipolar Disorder Altrecht Utrecht the Netherlands

Oxford Health NHS Foundation Trust Warneford Hospital Oxford UK

Psychiatric and Neurodevelopmental Genetics Unit Center for Genomic Medicine Massachusetts General Hospital and Harvard Medical School Boston MA USA

Psychiatric and Neurodevelopmental Genetics Unit Massachusetts General Hospital Boston MA USA

Psychiatric Genetics Unit Group of Psychiatry Mental Health and Addictions Vall d´Hebron Research Institut Universitat Autònoma de Barcelona Barcelona Spain

Psychiatry Altrecht Utrecht the Netherlands

Psychiatry and the Behavioral Sciences University of Southern California Los Angeles CA USA

Psychiatry Berkshire Healthcare NHS Foundation Trust Bracknell UK

Psychiatry Brain Center UMC Utrecht Utrecht the Netherlands

Psychiatry GGZ inGeest Amsterdam the Netherlands

Psychiatry Harvard Medical School Boston MA USA

Psychiatry Indiana University School of Medicine Indianapolis IN USA

Psychiatry North East London NHS Foundation Trust Ilford UK

Psychiatry Psychiatrisches Zentrum Nordbaden Wiesloch Germany

Psychiatry St Olavs University Hospital Trondheim Norway

Psychiatry University of California San Francisco San Francisco CA USA

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Psychiatry VU Medisch Centrum Amsterdam the Netherlands

Psychological Medicine University of Worcester Worcester UK

Psychosis Research Unit Aarhus University Hospital Psychiatry Risskov Denmark

Queensland Brain Institute The University of Queensland Brisbane Queensland Australia

Research and Communication Unit for Musculoskeletal Health Division of Clinical Neuroscience Oslo University Hospital Oslo Norway

Research Institute Lindner Center of HOPE Mason OH USA

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Russian Academy of Medical Sciences Mental Health Research Center Moscow Russian Federation

SA MRC Unit on Risk and Resilience in Mental Disorders Department of Psychiatry Stellenbosch University Stellenbosch South Africa

SAMRC Unit on Risk and Resilience in Mental Disorders Department of Psychiatry and Neuroscience Institute University of Cape Town Cape Town South Africa

Samsung Advanced Institute for Health Sciences and Technology Samsung Medical Center Sungkyunkwan University Seoul South Korea

School of Medical Sciences University of New South Wales Sydney New South Wales Australia

School of Psychiatry University of New South Wales Sydney New South Wales Australia

School of Psychology The University of Queensland Brisbane Queensland Australia

Social Genetic and Developmental Psychiatry Centre King's College London London UK

South London and Maudsley NHS Foundation Trust Bethlem Royal Hospital Beckenham UK

Stanley Center for Psychiatric Research Broad Institute Cambridge MA USA

Systems Genetics Working Group Department of Genetics Stellenbosch University Stellenbosch South Africa

The Florey Institute of Neuroscience and Mental Health The University of Melbourne Parkville Victoria Australia

UCL Genetics Institute University College London London UK

Université de Paris INSERM Optimisation Thérapeutique en Neuropsychopharmacologie UMRS 1144 Paris France

University of Liverpool Liverpool UK

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