Bipolar disorder is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 bipolar disorder risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci and prioritized 17 likely causal SNPs for bipolar disorder. We mapped these SNPs to genes and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci and results from rare variant exome sequencing in bipolar disorder. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment, including SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, FKBP2, RASGRP1, FURIN, FES, MED24 and THRA among others in bipolar disorder. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of bipolar disorder polygenic risk scores across diverse populations and present a high-throughput fine-mapping pipeline.

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

Analytic and Translational Genetics Unit Massachusetts General Hospital Boston MA USA

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

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

Center for Mind Brain and Behavior University of Marburg and Justus Liebig University Giessen Giessen Germany

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

Centre for Human Genetics University of Marburg Marburg Germany

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

Centre for Precision Psychiatry University of Oslo Oslo Norway

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

Charles Bronfman Institute for Personalized Medicine Icahn School of Medicine at Mount Sinai New York City NY USA

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

Clinical Research Center Shizuoka General Hospital Shizuoka Japan

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 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 Digital Health Samsung Advanced Institute for Health Sciences and Technology Sungkyunkwan University Samsung Medical Center Seoul Republic of Korea

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 City NY USA

Department of Genetics and Genomics United Arab Emirates University College of Medicine and Health Sciences Al Ain United Arab Emirates

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

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

Department of Medical and Molecular Genetics Indiana University Indianapolis IN USA

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medicine and Surgery Kore University of Enna Enna Italy

Department of Mental Health Hospital Universitari Vall d´Hebron Barcelona Spain

Department of Neurology Klinikum rechts der Isar School of Medicine Technical University of Munich Munich Germany

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

Department of Neuroscience SUNY Upstate Medical University Syracuse NY USA

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

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

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

Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine Baltimore MD USA

Department of Psychiatry and Behavioral Sciences SUNY Upstate Medical University Syracuse NY USA

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 Irvin CA USA

Department of Psychiatry and Neurobehavioural Science University College Cork Cork Ireland

Department of Psychiatry and Psychology Mayo Clinic Rochester MN USA

Department of Psychiatry and Psychotherapy Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

Department of Psychiatry and Psychotherapy Charité Universitätsmedizin Berlin Germany

Department of Psychiatry and Psychotherapy University Medical Center Göttingen Göttingen Germany

Department of Psychiatry and Psychotherapy University of Marburg Marburg Germany

Department of Psychiatry Dalhousie University Halifax Nova Scotia Canada

Department of Psychiatry Fujita Health University School of Medicine Toyoake Japan

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

Department of Psychiatry Massachusetts General Hospital Boston MA USA

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

Department of Psychiatry University of British Columbia Vancouver British Columbia Canada

Department of Psychiatry University of California San Diego La Jolla CA USA

Department of Psychiatry University of Melbourne Melbourne Victoria Australia

Department of Psychiatry University of Münster Münster Germany

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

Department of Psychological Sciences University of Missouri Columbia MO USA

Department of Psychology Emory University Atlanta GA USA

Department of Quantitative Health Sciences Mayo Clinic Rochester MN USA

Department of Translational Research in Psychiatry Max Planck Institute of Psychiatry Munich Germany

Departments of Psychiatry and Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN USA

Discipline of Psychiatry and Mental Health School of Clinical Medicine Faculty of Medicine and Health University of New South Wales Sydney New South Wales Australia

Division of Clinical Research Massachusetts General Hospital Boston MA USA

Division of Mental Health and Addiction Oslo University Hospital Oslo Norway

Division of Psychiatry Centre for Clinical Brain Sciences The University of Edinburgh Edinburgh UK

Division of Psychiatry University College London London UK

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

Faculty of Medicina and Health Sciences Department of Pathology Clinical Bioinformatics Unit Erasmus University Medical Center Rotterdam the Netherlands

Functional Genomics Laboratory School of Medicine University of California Irvine Irvine CA USA

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

German Center for Mental Health partner site Mannheim Heidelberg Ulm Heidelberg Germany

Hector Institute for Artificial Intelligence in Psychiatry Central Institute of Mental Health Medical Faculty Mannheim Heidelberg University Mannheim Germany

HudsonAlpha Institute for Biotechnology Huntsville AL USA

Indiana University School of Medicine Indianapolis IN USA

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

Institute for Translational Psychiatry University of Münster Münster Germany

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Medical Genetics and Pathology University Hospital Basel Basel Switzerland

Institute of Neuroscience and Medicine Research Centre Jülich Jülich Germany

Institute of Neuroscience and Physiology University of Gothenburg Gothenburg Sweden

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

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

ISGlobal Barcelona Spain

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

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

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

Mental Health Department University Regional Hospital Biomedicine Institute Málaga Spain

Munich Cluster for Systems Neurology Munich Germany

National Institute of Mental Health Klecany Czech Republic

Neuropsychiatric Genetics Research Group Department of Psychiatry and Trinity Translational Medicine Institute Trinity College Dublin Dublin Ireland

Neuroscience Research Australia Sydney New South Wales Australia

NIHR Maudsley Biomedical Research Centre South London and Maudsley NHS Foundation Trust London UK

Oasi Research Institute IRCCS Troina Italy

Programa SJD MIND Escoles Hospital Sant Joan de Déu Institut de Recerca Sant Joan de Déu Esplugues de Llobregat Spain

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 Harvard Medical School Boston MA USA

Psychological Medicine University of Worcester Worcester UK

Research Institute Lindner Center of HOPE Mason OH USA

Ronald M Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York City NY USA

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 Sungkyunkwan University Samsung Medical Center Seoul Republic of Korea

School of Biomedical Sciences Faculty of Medicine and Health University of New South Wales Sydney New South Wales Australia

School of Clinical Medicine Discipline of Psychiatry and Mental Health 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

Stanley Center for Psychiatric Research Broad Institute Cambridge MA USA

Stark Neurosciences Research Institute Indiana University School of Medicine Indianapolis IN USA

SUNY Downstate Health Sciences University Brooklyn NY USA

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

The Department of Applied Genetics The School of Pharmaceutical Sciences University of Shizuoka Shizuoka Japan

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

University of Newcastle Newcastle New South Wales Australia

University of Paris Est Créteil INSERM IMRB Translatiol Neuropsychiatry Créteil France

University of Queensland Brisbane Queensland Australia

University of Western Australia Nedlands Western Australia Australia

Zayed Center for Health Sciences United Arab Emirates University Al Ain United Arab Emirates

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medRxiv. 2024 Sep 17:2024.02.12.24302716. doi: 10.1101/2024.02.12.24302716. PubMed

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