Genomics yields biological and phenotypic insights into bipolar disorder

O’Connell KS, Koromina M, van der Veen T, Boltz T, David FS, Yang JMK, Lin KH, Wang X, Coleman JR, Mitchell BL, McGrouther CC, Rangan AV, Lind PA, Koch E, Harder A, Parker N, Bendl J, Adorjan K, Agerbo E, Albani D, Alemany S, Alliey-Rodriguez N, Als TD, Andlauer TF, Antoniou A, Ask H, Bass N, Bauer M, Beins EC, Bigdeli TB, Pedersen CB, Boks MP, Børte S, Bosch R, Brum M, Brumpton BM, Brunkhorst-Kanaan N, Budde M, Bybjerg-Grauholm J, Byerley W, Cabana-Domínguez J, Cairns MJ, Carpiniello B, Casas M, Cervantes P, Chatzinakos C, Chen HC, Clarence T, Clarke TK, Claus I, Coombes B, Corfield EC, Cruceanu C, Cuellar-Barboza A, Czerski PM, Dafnas K, Dale AM, Dalkner N, Degenhardt F, DePaulo JR, Djurovic S, Drange OK, Escott-Price V, Fanous AH, Fellendorf FT, Ferrier IN, Forty L, Frank J, Frei O, Freimer NB, Fullard JF, Garnham J, Gizer IR, Gordon SD, Gordon-Smith K, Greenwood TA, Grove J, Guzman-Parra J, Ha TH, Hahn T, Haraldsson M, Hautzinger M, Havdahl A, Heilbronner U, Hellgren D, Herms S, Hickie IB, Hoffmann P, Holmans PA, Huang MC, Ikeda M, Jamain S, Johnson JS, Jonsson L, Kalman JL, Kamatani Y, Kennedy JL, Kim E, Kim J, Kittel-Schneider S, Knowles JA, Kogevinas M, Kranz TM, Krebs K, Kushner SA, Lavebratt C, Lawrence J, Leber M, Lee HJ, Liao C, Lucae S, Lundberg M, MacIntyre DJ, Maier W, Maihofer AX, Malaspina D, Manchia M, Maratou E, Martinsson L, Mattheisen M, McGregor NW, McInnis MG, McKay JD, Medeiros H, Meyer-Lindenberg A, Millischer V, Morris DW, Moutsatsou P, Mühleisen TW, O’Donovan C, Olsen CM, Panagiotaropoulou G, Papiol S, Pardiñas AF, Park HY, Perry A, Pfennig A, Pisanu C, Potash JB, Quested D, Rapaport MH, Regeer EJ, Rice JP, Rivera M, Schulte EC, Senner F, Shadrin A, Shilling PD, Sigurdsson E, Sindermann L, Sirignano L, Siskind D, Slaney C, Sloofman LG, Smeland OB, Smith DJ, Sobell JL, Soler Artigas M, Stein DJ, Stein F, Su MH, Sung H, Świątkowska B, Terao C, Tesfaye M, Tesli M, Thorgeirsson TE, Thorp JG, Toma C, Tondo L, Tooney PA, Tsai SJ, Tsermpini EE, Vawter MP, Vedder H, Vreeker A, Walters JT, Winsvold BS, Witt SH, Won HH, Ye R, Young AH, Zandi PP, Zillich L, Huang GD, Harvey PD, Aslan M, Kim DJ, Cheon MJ, Kang JH, Lee YK, Kim JW, Lee BC, Adolfsson R, Alda M, Alfredsson L, Backlund L, Baune BT, Bellivier F, Bengesser S, Berrettini WH, Biernacka JM, Boehnke M, Børglum AD, Breen G, Carr VJ, Catts S, Cichon S, Corvin A, Craddock N, Dannlowski U, Dikeos D, Etain B, Ferentinos P, Frye M, Fullerton JM, Gawlik M, Gershon ES, Goes FS, Green MJ, Grigoroiu-Serbanescu M, Hauser J, Henskens FA, Hjerling-Leffler J, Hougaard DM, Hveem K, Iwata N, Jones I, Jones LA, Kahn RS, Kelsoe JR, Kircher T, Kirov G, Kuo PH, Landén M, Leboyer M, Li QS, Lissowska J, Lochner C, Loughland C, Luykx JJ, Martin NG, Mathews CA, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Medland SE, Melle I, Milani L, Mitchell PB, Morken G, Mors O, Mortensen PB, Müller-Myhsok B, Myers RM, Myung W, Neale BM, Nievergelt CM, Nordentoft M, Nöthen MM, Nurnberger JI, O’Donovan MC, Oedegaard KJ, Olsson T, Owen MJ, Paciga SA, Pantelis C, Pato CN, Pato MT, Patrinos GP, Pawlak JM, Ramos-Quiroga JA, Reif A, Reininghaus EZ, Ribasés M, Rietschel M, Ripke S, Rouleau GA, Roussos P, Saito T, Schall U, Schalling M, Schofield PR, Schulze TG, Scott LJ, Scott RJ, Serretti A, Smoller JW, Squassina A, Stahl EA, Stefansson H, Stefansson K, Stordal E, Streit F, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Waldman ID, Weickert CS, Weickert TW, Werge T, Whiteman DC, Zwart JA, Edenberg HJ, McQuillin A, Forstner AJ, Mullins N, Di Florio A, Ophoff RA, Andreassen OA (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Book Volume: 639

Pages Range: 968-975

Journal Issue: 8056

DOI: 10.1038/s41586-024-08468-9

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.

Involved external institutions

Lundbeck Foundation Initiative for Integrative Psychiatric Research Denmark (DK) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Oslo Norway (NO) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Altrecht Netherlands (NL) University of Stellenbosch / Universiteit van Stellenbosch South Africa (ZA) University of Newcastle (UoN) Australia (AU) Indiana University – Purdue University Indianapolis United States (USA) (US) University College London (UCL) United Kingdom (GB) Washington University in St. Louis United States (USA) (US) Universitätsklinikum Bonn Germany (DE) Icahn School of Medicine at Mount Sinai United States (USA) (US) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) Universidad de Granada Spain (ES) Cardiff University United Kingdom (GB) Klinikum der Universität München (LMU Klinikum) Germany (DE) University of California Los Angeles (UCLA) United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Karolinska Institute Sweden (SE) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Université Sorbonne Paris Cité France (FR) Medizinische Universität Graz Austria (AT) University of Pennsylvania (UPenn) United States (USA) (US) Mayo Clinic United States (USA) (US) University of Michigan United States (USA) (US) King’s College London United Kingdom (GB) University of New South Wales (UNSW) Australia (AU) University of Queensland Australia (AU) Trinity College Dublin Ireland (IE) Eginition Hospital Greece (GR) Neuroscience Research Australia NeuRA Australia (AU) Universitätsklinikum Würzburg Germany (DE) University of Chicago United States (USA) (US) National Institute of Mental Health Information Resource Center United States (USA) (US) University of Tartu Estonia (EE) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) Cardiovascular Research Foundation United States (USA) (US) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) Ruprecht-Karls-Universität Heidelberg Germany (DE) Università degli Studi di Cagliari Italy (IT) Fujita Health University Japan (JP) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) University Of Worcester United Kingdom (GB) Johns Hopkins Hospital United States (USA) (US) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Centre for Addiction and Mental Health (CAMH) Canada (CA) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Emory University United States (USA) (US) Philipps-Universität Marburg Germany (DE) National Taiwan University Hospital (NTUH) / 國立台灣大學醫學院附設醫院 Taiwan (TW) Paris-Est Créteil University / Université Paris-Est Créteil Val-de-Marne (UPEC) / Université Paris XII-Val-de-Marne / University Paris 12 Marne la Vallée France (FR) Janssen Global Services, LLC United States (USA) (US) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) SUNY Downstate Medical Center United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) The Jane and Terry Semel Institute for Neuroscience and Human Behavior United States (USA) (US) Mario Negri Institute for Pharmacological Research (IRCCS) / Istituto di Ricerche Farmacologiche Mario Negri Italy (IT) University of California San Francisco (UCSF) United States (USA) (US) Hospital Sant Joan de Déu Barcelona Spain (ES) Klinikum rechts der Isar Germany (DE) National and Kapodistrian University of Athens Greece (GR) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Norwegian Institute of Public Health (NIPH) / Folkehelseinstituttet Norway (NO) Dalhousie University Canada (CA) University of Missouri-Columbia (Mizzou) United States (USA) (US) University of Edinburgh United Kingdom (GB) Universidad Autónoma de Nuevo León Mexico (MX) Seoul National University Bundang Hospital (SNUBH) / 분당 서울대병원 Korea, Republic of (KR) University College Cork (UCC) Ireland (IE) Rutgers, The State University of New Jersey United States (USA) (US) Instituto de Salud Global de Barcelona (ISGlobal) Spain (ES) Erasmus University Medical Center (MC) Netherlands (NL) University of Iceland (UI) / Háskóli Íslands Iceland (IS) 23andMe United States (USA) (US) North East London NHS Foundation Trust United Kingdom (GB) Universitätsklinikum Köln Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Korea University / 고려대학교 Korea, Republic of (KR) Massachusetts General Hospital United States (USA) (US) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) HudsonAlpha United States (USA) (US) University of Sydney (USYD) Australia (AU) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Taipei City Hospital Taiwan (TW) Pfizer, Inc. United States (USA) (US) University of Patras (UPATRAS) Greece (GR) Nagoya University / 名古屋大学 Japan (JP) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) University of Southern California (USC) United States (USA) (US) University of Cape Town (UCT) South Africa (ZA) University of Gothenburg / Göteborgs universitet Sweden (SE) McGill University Canada (CA) Virginia Commonwealth University (VCU) United States (USA) (US) University of Tokyo Japan (JP) Nofer Institute of Occupational Medicine (NIOM) Poland (PL) IMS RIKEN Center for Integrative Medical Sciences Japan (JP) deCODE genetics Iceland (IS) Oslo University Hospital, Ullevål / Oslo universitetssykehus, Ullevål Norway (NO) Universitätsklinikum Mannheim / University Medical Centre Mannheim (Universitätsmedizin Mannheim) Germany (DE) University of Arizona United States (USA) (US) Harvard University United States (USA) (US) Newcastle University United Kingdom (GB) Taipei Veterans General Hospital / 台北榮民總醫院 Taiwan (TW) University of Galway (NUIG) / Ollscoil na Gaillimhe Ireland (IE) University of California Irvine United States (USA) (US) Psychiatrisches Krankenhaus Rickling Germany (DE) Sungkyunkwan University (SKKU) Korea, Republic of (KR) University of Florida United States (USA) (US) Lindner Center of HOPE United States (USA) (US) The University of Melbourne Australia (AU) Universität Basel Switzerland (CH) Veterans Health Administration (VHA) United States (USA) (US) Miami VA Healthcare System United States (USA) (US) VA Connecticut Healthcare System United States (USA) (US) Genoplan Korea, Republic of (KR) Namsos Hospital Norway (NO) Charité - Universitätsmedizin Berlin Germany (DE) Umeå University Sweden (SE) Kore University of Enna / Università degli Studi di Enna Kore Italy (IT) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US)

How to cite

APA:

O’Connell, K.S., Koromina, M., van der Veen, T., Boltz, T., David, F.S., Yang, J.M.K.,... Andreassen, O.A. (2025). Genomics yields biological and phenotypic insights into bipolar disorder. Nature, 639(8056), 968-975. https://doi.org/10.1038/s41586-024-08468-9

MLA:

O’Connell, Kevin S., et al. "Genomics yields biological and phenotypic insights into bipolar disorder." Nature 639.8056 (2025): 968-975.

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