Genomics yields biological and phenotypic insights into bipolar disorder

Kevin S. O’Connell (), Maria Koromina, Tracey van der Veen, Toni Boltz, Friederike S. David, Jessica Mei Kay Yang, Keng-Han Lin, Xin Wang, Jonathan R. I. Coleman, Brittany L. Mitchell, Caroline C. McGrouther, Aaditya V. Rangan, Penelope A. Lind, Elise Koch, Arvid Harder, Nadine Parker, Jaroslav Bendl, Kristina Adorjan, Esben Agerbo, Diego Albani, Silvia Alemany, Ney Alliey-Rodriguez, Thomas D. Als, Till F. M. Andlauer, Anastasia Antoniou, Helga Ask, Nicholas Bass, Michael Bauer, Eva C. Beins, Tim B. Bigdeli, Carsten Bøcker Pedersen, Marco P. Boks, Sigrid Børte, Rosa Bosch, Murielle Brum, Ben M. Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Judit Cabana-Domínguez, Murray J. Cairns, Bernardo Carpiniello, Miquel Casas, Pablo Cervantes, Chris Chatzinakos, Hsi-Chung Chen, Tereza Clarence, Toni-Kim Clarke, Isabelle Claus, Brandon Coombes, Elizabeth C. Corfield, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Piotr M. Czerski, Konstantinos Dafnas, Anders M. Dale, Nina Dalkner, Franziska Degenhardt, J. Raymond DePaulo, Srdjan Djurovic, Ole Kristian Drange, Valentina Escott-Price, Ayman H. Fanous, Frederike T. Fellendorf, I. Nicol Ferrier, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, John F. Fullard, Julie Garnham, Ian R. Gizer, Scott D. Gordon, Katherine Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, José Guzman-Parra, Tae Hyon Ha, Tim Hahn, Magnus Haraldsson, Martin Hautzinger, Alexandra Havdahl, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Ian B. Hickie, Per Hoffmann, Peter A. Holmans, Ming-Chyi Huang, Masashi Ikeda, Stéphane Jamain, Jessica S. Johnson, Lina Jonsson, Janos L. Kalman, Yoichiro Kamatani, James L. Kennedy, Euitae Kim, Jaeyoung Kim, Sarah Kittel-Schneider, James A. Knowles, Manolis Kogevinas, Thorsten M. Kranz, Kristi Krebs, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Wolfgang Maier, Adam X. Maihofer, Dolores Malaspina, Mirko Manchia, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Nathaniel W. McGregor, Melvin G. McInnis, James D. McKay, Helena Medeiros, Andreas Meyer-Lindenberg, Vincent Millischer, Derek W. Morris, Paraskevi Moutsatsou, Thomas W. Mühleisen, Claire O’Donovan, Catherine M. Olsen, Georgia Panagiotaropoulou, Sergi Papiol, Antonio F. Pardiñas, Hye Youn Park, Amy Perry, Andrea Pfennig, Claudia Pisanu, James B. Potash, Digby Quested, Mark H. Rapaport, Eline J. Regeer, John P. Rice, Margarita Rivera, Eva C. Schulte, Fanny Senner, Alexey Shadrin, Paul D. Shilling, Engilbert Sigurdsson, Lisa Sindermann, Lea Sirignano, Dan Siskind, Claire Slaney, Laura G. Sloofman, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, Maria Soler Artigas, Dan J. Stein, Frederike Stein, Mei-Hsin Su, Heejong Sung, Beata Świątkowska, Chikashi Terao, Markos Tesfaye, Martin Tesli, Thorgeir E. Thorgeirsson, Jackson G. Thorp, Claudio Toma, Leonardo Tondo, Paul A. Tooney, Shih-Jen Tsai, Evangelia Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Annabel Vreeker, James T. R. Walters, Bendik S. Winsvold, Stephanie H. Witt, Hong-Hee Won, Robert Ye, Allan H. Young, Peter P. Zandi, Lea Zillich, Rolf Adolfsson, Martin Alda, Lars Alfredsson, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Joanna M. Biernacka, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans A. Henskens, Jens Hjerling-Leffler, David M. Hougaard, Kristian Hveem, Nakao Iwata, Ian Jones, Lisa A. Jones, René S. Kahn, John R. Kelsoe, Tilo Kircher, George Kirov, Po-Hsiu Kuo, Mikael Landén, Marion Leboyer, Qingqin S. Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Jurjen J. Luykx, Nicholas G. Martin, Carol A. Mathews, Fermin Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Sarah E. Medland, Ingrid Melle, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M. Myers, Woojae Myung, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, John I. Nurnberger, Michael C. O’Donovan, Ketil J. Oedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Christos Pantelis, Carlos N. Pato, Michele T. Pato, George P. Patrinos, Joanna M. Pawlak, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Panos Roussos, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Jordan W. Smoller, Alessio Squassina, Eli A. Stahl, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Cynthia S. Weickert, Thomas W. Weickert, Thomas Werge, David C. Whiteman, John-Anker Zwart, Howard J. Edenberg, Andrew McQuillin, Andreas J. Forstner, Niamh Mullins, Arianna Di Florio, Roel A. Ophoff and Ole A. Andreassen ()
Additional contact information
Kevin S. O’Connell: Oslo University Hospital
Maria Koromina: Icahn School of Medicine at Mount Sinai
Tracey van der Veen: University College London
Toni Boltz: University of California Los Angeles
Friederike S. David: School of Medicine and University Hospital Bonn
Jessica Mei Kay Yang: Cardiff University
Keng-Han Lin: 23andMe Inc.
Xin Wang: 23andMe Inc.
Jonathan R. I. Coleman: King’s College London
Brittany L. Mitchell: QIMR Berghofer Medical Research Institute
Caroline C. McGrouther: New York University
Aaditya V. Rangan: New York University
Penelope A. Lind: QIMR Berghofer Medical Research Institute
Elise Koch: Oslo University Hospital
Arvid Harder: Karolinska Institutet
Nadine Parker: Oslo University Hospital
Jaroslav Bendl: Icahn School of Medicine at Mount Sinai
Kristina Adorjan: LMU Munich
Esben Agerbo: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Diego Albani: Istituto Di Ricerche Farmacologiche Mario Negri IRCCS
Silvia Alemany: Biomedical Network Research Centre on Mental Health (CIBERSAM)
Ney Alliey-Rodriguez: University of Chicago
Thomas D. Als: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Till F. M. Andlauer: Technical University of Munich
Anastasia Antoniou: Attikon General Hospital
Helga Ask: Norwegian Institute of Public Health
Nicholas Bass: University College London
Michael Bauer: Technische Universität Dresden
Eva C. Beins: School of Medicine and University Hospital Bonn
Tim B. Bigdeli: SUNY Downstate Health Sciences University
Carsten Bøcker Pedersen: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Marco P. Boks: Brain Center UMC Utrecht
Sigrid Børte: Oslo University Hospital, Ullevål
Rosa Bosch: Biomedical Network Research Centre on Mental Health (CIBERSAM)
Murielle Brum: University Hospital Frankfurt
Ben M. Brumpton: Norwegian University of Science and Technology
Nathalie Brunkhorst-Kanaan: University Hospital Frankfurt
Monika Budde: LMU Munich
Jonas Bybjerg-Grauholm: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
William Byerley: University of California San Francisco
Judit Cabana-Domínguez: Biomedical Network Research Centre on Mental Health (CIBERSAM)
Murray J. Cairns: The University of Newcastle
Bernardo Carpiniello: University of Cagliari
Miquel Casas: Institut de Recerca Sant Joan de Déu
Pablo Cervantes: McGill University Health Center
Chris Chatzinakos: SUNY Downstate Health Sciences University
Hsi-Chung Chen: National Taiwan University Hospital
Tereza Clarence: Icahn School of Medicine at Mount Sinai
Toni-Kim Clarke: University of Edinburgh
Isabelle Claus: School of Medicine and University Hospital Bonn
Brandon Coombes: Mayo Clinic
Elizabeth C. Corfield: Norwegian Institute of Public Health
Cristiana Cruceanu: McGill University Health Center
Alfredo Cuellar-Barboza: Universidad Autonoma de Nuevo Leon
Piotr M. Czerski: Poznan University of Medical Sciences
Konstantinos Dafnas: Attikon General Hospital
Anders M. Dale: University of California
Nina Dalkner: Medical University of Graz
Franziska Degenhardt: School of Medicine and University Hospital Bonn
J. Raymond DePaulo: Johns Hopkins University School of Medicine
Srdjan Djurovic: Oslo University Hospital Ullevål
Ole Kristian Drange: University of Oslo
Valentina Escott-Price: Cardiff University
Ayman H. Fanous: University of Arizona College of Medicine-Phoenix
Frederike T. Fellendorf: Medical University of Graz
I. Nicol Ferrier: Newcastle University
Liz Forty: Cardiff University
Josef Frank: Heidelberg University
Oleksandr Frei: Oslo University Hospital
Nelson B. Freimer: Semel Institute for Neuroscience and Human Behavior
John F. Fullard: Icahn School of Medicine at Mount Sinai
Julie Garnham: Dalhousie University
Ian R. Gizer: University of Missouri
Scott D. Gordon: QIMR Berghofer Medical Research Institute
Katherine Gordon-Smith: University of Worcester
Tiffany A. Greenwood: University of California San Diego
Jakob Grove: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
José Guzman-Parra: Biomedicine Institute (IBIMA)
Tae Hyon Ha: Seoul National University Bundang Hospital
Tim Hahn: University of Münster
Magnus Haraldsson: University of Iceland
Martin Hautzinger: Eberhard Karls Universität Tübingen
Alexandra Havdahl: Norwegian Institute of Public Health
Urs Heilbronner: LMU Munich
Dennis Hellgren: Karolinska Institutet
Stefan Herms: School of Medicine and University Hospital Bonn
Ian B. Hickie: The University of Sydney
Per Hoffmann: School of Medicine and University Hospital Bonn
Peter A. Holmans: Cardiff University
Ming-Chyi Huang: Taipei City Hospital
Masashi Ikeda: Nagoya University Graduate School of Medicine
Stéphane Jamain: Translational Neuropsychiatry
Jessica S. Johnson: Icahn School of Medicine at Mount Sinai
Lina Jonsson: University of Gothenburg
Janos L. Kalman: LMU Munich
Yoichiro Kamatani: The University of Tokyo
James L. Kennedy: Centre for Addiction and Mental Health
Euitae Kim: Seoul National University Bundang Hospital
Jaeyoung Kim: Seoul National University Bundang Hospital
Sarah Kittel-Schneider: University College Cork
James A. Knowles: Rutgers University
Manolis Kogevinas: ISGlobal
Thorsten M. Kranz: University Hospital Frankfurt
Kristi Krebs: University of Tartu
Steven A. Kushner: University Medical Center Rotterdam
Catharina Lavebratt: Karolinska Institutet
Jacob Lawrence: North East London NHS Foundation Trust
Markus Leber: University Hospital Cologne
Heon-Jeong Lee: Korea University College of Medicine
Calwing Liao: Massachusetts General Hospital
Susanne Lucae: Max Planck Institute of Psychiatry
Martin Lundberg: Karolinska Institutet
Donald J. MacIntyre: The University of Edinburgh
Wolfgang Maier: School of Medicine and University Hospital Bonn
Adam X. Maihofer: University of California San Diego
Dolores Malaspina: Icahn School of Medicine at Mount Sinai
Mirko Manchia: University of Cagliari
Eirini Maratou: Attikon General Hospital
Lina Martinsson: Karolinska Institutet
Manuel Mattheisen: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Nathaniel W. McGregor: Stellenbosch University
Melvin G. McInnis: University of Michigan
James D. McKay: International Agency for Research on Cancer
Helena Medeiros: SUNY Downstate Medical Center College of Medicine
Andreas Meyer-Lindenberg: University of Heidelberg
Vincent Millischer: Karolinska Institutet
Derek W. Morris: University of Galway
Paraskevi Moutsatsou: Attikon General Hospital
Thomas W. Mühleisen: University of Basel
Claire O’Donovan: Dalhousie University
Catherine M. Olsen: QIMR Berghofer Medical Research Institute
Georgia Panagiotaropoulou: Charité-Universitätsmedizin
Sergi Papiol: LMU Munich
Antonio F. Pardiñas: Cardiff University
Hye Youn Park: Seoul National University Bundang Hospital
Amy Perry: University of Worcester
Andrea Pfennig: Technische Universität Dresden
Claudia Pisanu: University of Cagliari
James B. Potash: Johns Hopkins University School of Medicine
Digby Quested: Warneford Hospital
Mark H. Rapaport: Emory University School of Medicine
Eline J. Regeer: Altrecht
John P. Rice: Washington University in Saint Louis
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Fanny Senner: LMU Munich
Alexey Shadrin: Oslo University Hospital
Paul D. Shilling: University of California San Diego
Engilbert Sigurdsson: University of Iceland
Lisa Sindermann: School of Medicine and University Hospital Bonn
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Dan Siskind: University of Queensland
Claire Slaney: Dalhousie University
Laura G. Sloofman: Icahn School of Medicine at Mount Sinai
Olav B. Smeland: Oslo University Hospital
Daniel J. Smith: University of Edinburgh
Janet L. Sobell: University of Southern California
Maria Soler Artigas: Biomedical Network Research Centre on Mental Health (CIBERSAM)
Dan J. Stein: University of Cape Town
Frederike Stein: University of Marburg
Mei-Hsin Su: Virginia Commonwealth University
Heejong Sung: National Institute of Mental Health
Beata Świątkowska: Nofer Institute of Occupational Medicine
Chikashi Terao: RIKEN Center for Integrative Medical Sciences
Markos Tesfaye: Oslo University Hospital
Martin Tesli: Oslo University Hospital
Thorgeir E. Thorgeirsson: deCODE Genetics/Amgen
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Leonardo Tondo: Harvard Medical School
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Shih-Jen Tsai: Taipei Veterans General Hospital
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James T. R. Walters: Cardiff University
Bendik S. Winsvold: Norwegian University of Science and Technology
Stephanie H. Witt: Heidelberg University
Hong-Hee Won: Samsung Medical Center
Robert Ye: Massachusetts General Hospital
Allan H. Young: King’s College London
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Michael Boehnke: University of Michigan
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Gerome Breen: King’s College London
Vaughan J. Carr: University of New South Wales
Stanley Catts: University of Queensland
Sven Cichon: School of Medicine and University Hospital Bonn
Aiden Corvin: Trinity College Dublin
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Fernando S. Goes: Johns Hopkins University School of Medicine
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Maria Grigoroiu-Serbanescu: Alexandru Obregia Clinical Psychiatric Hospital
Joanna Hauser: Poznan University of Medical Sciences
Frans A. Henskens: University of Newcastle
Jens Hjerling-Leffler: Karolinska Institutet
David M. Hougaard: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Kristian Hveem: Norwegian University of Science and Technology
Nakao Iwata: Fujita Health University School of Medicine
Ian Jones: Cardiff University
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René S. Kahn: Icahn School of Medicine at Mount Sinai
John R. Kelsoe: University of California San Diego
Tilo Kircher: University of Marburg
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Po-Hsiu Kuo: National Taiwan University Hospital
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Preben Bo Mortensen: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Bertram Müller-Myhsok: Max Planck Institute of Psychiatry
Richard M. Myers: HudsonAlpha Institute for Biotechnology
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Josep Antoni Ramos-Quiroga: Biomedical Network Research Centre on Mental Health (CIBERSAM)
Andreas Reif: University Hospital Frankfurt
Eva Z. Reininghaus: Medical University of Graz
Marta Ribasés: Biomedical Network Research Centre on Mental Health (CIBERSAM)
Marcella Rietschel: Heidelberg University
Stephan Ripke: Massachusetts General Hospital
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Ulrich Schall: The University of Newcastle
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Peter R. Schofield: Neuroscience Research Australia
Thomas G. Schulze: LMU Munich
Laura J. Scott: University of Michigan
Rodney J. Scott: University of Newcastle
Alessandro Serretti: Kore University of Enna
Jordan W. Smoller: Broad Institute
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Eli A. Stahl: Icahn School of Medicine at Mount Sinai
Hreinn Stefansson: deCODE Genetics/Amgen
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Eystein Stordal: Hospital Namsos
Fabian Streit: Heidelberg University
Patrick F. Sullivan: Karolinska Institutet
Gustavo Turecki: McGill University
Arne E. Vaaler: Sankt Olavs Hospital Universitetssykehuset i Trondheim
Eduard Vieta: CIBERSAM
John B. Vincent: Centre for Addiction and Mental Health
Irwin D. Waldman: Emory University
Cynthia S. Weickert: Neuroscience Research Australia
Thomas W. Weickert: Neuroscience Research Australia
Thomas Werge: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
David C. Whiteman: QIMR Berghofer Medical Research Institute
John-Anker Zwart: University of Oslo
Howard J. Edenberg: Indiana University School of Medicine
Andrew McQuillin: University College London
Andreas J. Forstner: School of Medicine and University Hospital Bonn
Niamh Mullins: Icahn School of Medicine at Mount Sinai
Arianna Di Florio: Cardiff University
Roel A. Ophoff: University of California Los Angeles
Ole A. Andreassen: Oslo University Hospital

Nature, 2025, vol. 639, issue 8056, 968-975

Abstract: Abstract Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60–80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

Date: 2025
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DOI: 10.1038/s41586-024-08468-9

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