Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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40562893
TITLE
Fine-mapping genomic loci refines bipolar disorder risk genes.
ABSTRACT
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.
© 2025. The Author(s).
DATE PUBLISHED
2025 Jul
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2023/12/22
accepted 2025/05/07
medline 2025/07/07 00:26
pubmed 2025/06/26 00:27
entrez 2025/06/25 23:19
pmc-release 2025/06/25
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Koromina M Koromina Maria M Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. maria.koromina@mssm.edu.
Ravi A Ravi Ashvin A Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Panagiotaropoulou G Panagiotaropoulou Georgia G Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
Schilder BM Schilder Brian M BM Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Humphrey J Humphrey Jack J Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Braun A Braun Alice A Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany.
Bidgeli T Bidgeli Tim T SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
Chatzinakos C Chatzinakos Chris C SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
Coombes BJ Coombes Brandon J BJ Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
Kim J Kim Jaeyoung J Department of Digital Health, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea.
Liu X Liu Xiaoxi X Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
Terao C Terao Chikashi C The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
O'Connell KS O'Connell Kevin S KS Centre for Precision Psychiatry, University of Oslo, Oslo, Norway.
Adams MJ Adams Mark J MJ Division of Psychiatry, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
Adolfsson R Adolfsson Rolf R Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, Sweden.
Alda M Alda Martin M National Institute of Mental Health, Klecany, Czech Republic.
Alfredsson L Alfredsson Lars L Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Andlauer TFM Andlauer Till F M TFM Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Andreassen OA Andreassen Ole A OA Centre for Precision Psychiatry, University of Oslo, Oslo, Norway.
Antoniou A Antoniou Anastasia A Second Department of Psychiatry, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Baune BT Baune Bernhard T BT The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
Bengesser S Bengesser Susanne S Medical University of Graz, Division of Psychiatry and Psychotherapeutic Medicine, Graz, Austria.
Biernacka J Biernacka Joanna J Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
Boehnke M Boehnke Michael M Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Bosch R Bosch Rosa R Programa SJD MIND Escoles, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain.
Cairns MJ Cairns Murray J MJ University of Newcastle, Newcastle, New South Wales, Australia.
Carr VJ Carr Vaughan J VJ School of Clinical Medicine, Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.
Casas M Casas Miquel M Programa SJD MIND Escoles, Hospital Sant Joan de Déu, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Spain.
Catts S Catts Stanley S University of Queensland, Brisbane, Queensland, Australia.
Cichon S Cichon Sven S Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany.
Corvin A Corvin Aiden A Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland.
Craddock N Craddock Nicholas N Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Dafnas K Dafnas Konstantinos K Second Department of Psychiatry, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Dalkner N Dalkner Nina N Medical University of Graz, Division of Psychiatry and Psychotherapeutic Medicine, Graz, Austria.
Dannlowski U Dannlowski Udo U Institute for Translational Psychiatry, University of Münster, Münster, Germany.
Degenhardt F Degenhardt Franziska F Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Duisburg, Germany.
Di Florio A Di Florio Arianna A Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Dikeos D Dikeos Dimitris D Second Department of Psychiatry, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Fellendorf FT Fellendorf Frederike Tabea FT Medical University of Graz, Division of Psychiatry and Psychotherapeutic Medicine, Graz, Austria.
Ferentinos P Ferentinos Panagiotis P Social, Genetic and Developmental Psychiatry Centre, King's College London, London, UK.
Forstner AJ Forstner Andreas J AJ Centre for Human Genetics, University of Marburg, Marburg, Germany.
Forty L Forty Liz L Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Frye M Frye Mark M Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.
Fullerton JM Fullerton Janice M JM School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, New South Wales, Australia.
Gawlik M Gawlik Micha M Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.
Gizer IR Gizer Ian R IR Department of Psychological Sciences, University of Missouri, Columbia, MO, USA.
Gordon-Smith K Gordon-Smith Katherine K Psychological Medicine, University of Worcester, Worcester, UK.
Green MJ Green Melissa J MJ 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.
Grigoroiu-Serbanescu M Grigoroiu-Serbanescu Maria M Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, Romania.
Guzman-Parra J Guzman-Parra José J Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Málaga, Spain.
Hahn T Hahn Tim T Institute for Translational Psychiatry, University of Münster, Münster, Germany.
Henskens F Henskens Frans F University of Newcastle, Newcastle, New South Wales, Australia.
Hillert J Hillert Jan J Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Jablensky AV Jablensky Assen V AV University of Western Australia, Nedlands, Western Australia, Australia.
Jones L Jones Lisa L Psychological Medicine, University of Worcester, Worcester, UK.
Jones I Jones Ian I Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Jonsson L Jonsson Lina L Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
Kelsoe JR Kelsoe John R JR Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
Kircher T Kircher Tilo T Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany.
Kirov G Kirov George G Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Kittel-Schneider S Kittel-Schneider Sarah S Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland.
Kogevinas M Kogevinas Manolis M ISGlobal, Barcelona, Spain.
Landén M Landén Mikael M Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Leboyer M Leboyer Marion M Department of Psychiatry and Addiction Medicine, Assistance Publique-Hôpitaux de Paris, Paris, France.
Lenger M Lenger Melanie M Medical University of Graz, Division of Psychiatry and Psychotherapeutic Medicine, Graz, Austria.
Lissowska J Lissowska Jolanta J Cancer Epidemiology and Prevention, M. Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
Lochner C Lochner Christine C SA MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, Stellenbosch, South Africa.
Loughland C Loughland Carmel C University of Newcastle, Newcastle, New South Wales, Australia.
MacIntyre DJ MacIntyre Donald J DJ Division of Psychiatry, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
Martin NG Martin Nicholas G NG School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
Maratou E Maratou Eirini E Medical School, Clinical Biochemistry Laboratory, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Mathews CA Mathews Carol A CA Department of Psychiatry and Genetics Institute, University of Florida, Gainesville, FL, USA.
Mayoral F Mayoral Fermin F Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Málaga, Spain.
McElroy SL McElroy Susan L SL Research Institute, Lindner Center of HOPE, Mason, OH, USA.
McGregor NW McGregor Nathaniel W NW Systems Genetics Working Group, Department of Genetics, Stellenbosch University, Stellenbosch, South Africa.
McIntosh A McIntosh Andrew A Division of Psychiatry, Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
McQuillin A McQuillin Andrew A Division of Psychiatry, University College London, London, UK.
Michie P Michie Patricia P University of Newcastle, Newcastle, New South Wales, Australia.
Mitchell PB Mitchell Philip B PB 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.
Moutsatsou P Moutsatsou Paraskevi P Medical School, Clinical Biochemistry Laboratory, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Mowry B Mowry Bryan B University of Queensland, Brisbane, Queensland, Australia.
Müller-Myhsok B Müller-Myhsok Bertram B Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Myers RM Myers Richard M RM HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
Nenadić I Nenadić Igor I Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Giessen, Germany.
Nievergelt CM Nievergelt Caroline M CM Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA.
Nöthen MM Nöthen Markus M MM Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
Nurnberger J Nurnberger John J Indiana University School of Medicine, Indianapolis, IN, USA.
'Donovan MO 'Donovan Michael O MO Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
'Donovan CO 'Donovan Claire O CO Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.
Ophoff RA Ophoff Roel A RA Department of Psychiatry and Biobehavioral Science, Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Owen MJ Owen Michael J MJ Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Pantelis C Pantelis Christos C Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia.
Pato C Pato Carlos C Institute for Genomic Health, SUNY Downstate Medical Center, College of Medicine, Brooklyn, NY, USA.
Pato MT Pato Michele T MT Institute for Genomic Health, SUNY Downstate Medical Center, College of Medicine, Brooklyn, NY, USA.
Patrinos GP Patrinos George P GP Faculty of Medicina and Health Sciences, Department of Pathology, Clinical Bioinformatics Unit, Erasmus University Medical Center, Rotterdam, the Netherlands.
Pawlak JM Pawlak Joanna M JM Department of Psychiatric Genetics, Department of Psychiatry, Poznan University of Medical Sciences, Poznan, Poland.
Perlis RH Perlis Roy H RH Division of Clinical Research, Massachusetts General Hospital, Boston, MA, USA.
Porichi E Porichi Evgenia E Second Department of Psychiatry, Attikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece.
Posthuma D Posthuma Danielle D Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, the Netherlands.
Ramos-Quiroga JA Ramos-Quiroga Josep Antoni JA Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addictions, Vall d´Hebron Research Institut (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Reif A Reif Andreas A Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
Reininghaus EZ Reininghaus Eva Z EZ Medical University of Graz, Division of Psychiatry and Psychotherapeutic Medicine, Graz, Austria.
Ribasés M Ribasés Marta M Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain.
Rietschel M Rietschel Marcella M Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Schall U Schall Ulrich U University of Newcastle, Newcastle, New South Wales, Australia.
Schofield PR Schofield Peter R PR 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.
Schulze TG Schulze Thomas G TG Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
Scott L Scott Laura L Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
Scott RJ Scott Rodney J RJ University of Newcastle, Newcastle, New South Wales, Australia.
Serretti A Serretti Alessandro A Oasi Research Institute-IRCCS, Troina, Italy.
Smoller JW Smoller Jordan W JW Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, USA.
Świątkowska B Świątkowska Beata B Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland.
Soler Artigas M Soler Artigas Maria M Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addictions, Vall d´Hebron Research Institut (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
Stein DJ Stein Dan J DJ SAMRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Streit F Streit Fabian F German Center for Mental Health (DZPG), partner site Mannheim/Heidelberg/Ulm, Heidelberg, Germany.
Toma C Toma Claudio C Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid and CSIC, Madrid, Spain.
Tooney P Tooney Paul P University of Newcastle, Newcastle, New South Wales, Australia.
Vawter MP Vawter Marquis P MP Department of Psychiatry and Human Behavior, School of Medicine, University of California Irvine, Irvin, CA, USA.
Vieta E Vieta Eduard E Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
Vincent JB Vincent John B JB Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Waldman ID Waldman Irwin D ID Department of Psychology, Emory University, Atlanta, GA, USA.
Weickert CS Weickert Cynthia Shannon CS Department of Neuroscience, SUNY Upstate Medical University, Syracuse, NY, USA.
Weickert T Weickert Thomas T Department of Neuroscience, SUNY Upstate Medical University, Syracuse, NY, USA.
Witt SH Witt Stephanie H SH Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Hong KS Hong Kyung Sue KS Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Ikeda M Ikeda Masashi M Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
Iwata N Iwata Nakao N Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
Won HH Won Hong-Hee HH Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, Republic of Korea.
Edenberg HJ Edenberg Howard J HJ Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA.
Ripke S Ripke Stephan S Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Raj T Raj Towfique T Estelle and Daniel Maggin Department of Neurology, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
Coleman JRI Coleman Jonathan R I JRI NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.
Mullins N Mullins Niamh N Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA. niamh.mullins@mssm.edu.
INVESTIGATORS
JOURNAL
VOLUME: 28
ISSUE: 7
TITLE: Nature neuroscience
ISOABBREVIATION: Nat Neurosci
YEAR: 2025
MONTH: Jul
DAY:
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1546-1726
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Nat Neurosci
COUNTRY: United States
ISSNLINKING: 1097-6256
NLMUNIQUEID: 9809671
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
UpdateOf medRxiv. 2024 Sep 17:2024.02.12.24302716. doi: 10.1101/2024.02.12.24302716. 38405768
GRANTS
GRANTID AGENCY COUNTRY
R01 MH124839 NIMH NIH HHS United States
S10 OD018522 NIH HHS United States
S10 OD026880 NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Bipolar Disorder genetics
Humans genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study methods
Polymorphism, Single Nucleotide genetics
Chromosome Mapping methods
Quantitative Trait Loci genetics
Multifactorial Inheritance genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
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