Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

Mullins N, Forstner AJ, O’Connell KS, Coombes B, Coleman JR, Qiao Z, Als TD, Bigdeli TB, Børte S, Bryois J, Charney AW, Drange OK, Gandal MJ, Hagenaars SP, Ikeda M, Kamitaki N, Kim M, Krebs K, Panagiotaropoulou G, Schilder BM, Sloofman LG, Steinberg S, Trubetskoy V, Winsvold BS, Won HH, Abramova L, Adorjan K, Agerbo E, Al Eissa M, Albani D, Alliey-Rodriguez N, Anjorin A, Antilla V, Antoniou A, Awasthi S, Baek JH, Bækvad-Hansen M, Bass N, Bauer M, Beins EC, Bergen SE, Birner A, Bøcker Pedersen C, Bøen E, Boks MP, Bosch R, Brum M, Brumpton BM, Brunkhorst-Kanaan N, Budde M, Bybjerg-Grauholm J, Byerley W, Cairns M, Casas M, Cervantes P, Clarke TK, Cruceanu C, Cuellar-Barboza A, Cunningham J, Curtis D, Czerski PM, Dale AM, Dalkner N, David FS, Degenhardt F, Djurovic S, Dobbyn AL, Douzenis A, Elvsåshagen T, Escott-Price V, Ferrier IN, Fiorentino A, Foroud TM, Forty L, Frank J, Frei O, Freimer NB, Frisén L, Gade K, Garnham J, Gelernter J, Giørtz Pedersen M, Gizer IR, Gordon SD, Gordon-Smith K, Greenwood TA, Grove J, Guzman-Parra J, Ha K, Haraldsson M, Hautzinger M, Heilbronner U, Hellgren D, Herms S, Hoffmann P, Holmans PA, Huckins L, Jamain S, Johnson JS, Kalman JL, Kamatani Y, Kennedy JL, Kittel-Schneider S, Knowles JA, Kogevinas M, Koromina M, Kranz TM, Kranzler HR, Kubo M, Kupka R, Kushner SA, Lavebratt C, Lawrence J, Leber M, Lee HJ, Lee PH, Levy SE, Lewis C, Liao C, Lucae S, Lundberg M, MacIntyre DJ, Magnusson SH, Maier W, Maihofer A, Malaspina D, Maratou E, Martinsson L, Mattheisen M, McCarroll SA, McGregor NW, McGuffin P, McKay JD, Medeiros H, Medland SE, Millischer V, Montgomery GW, Moran JL, Morris DW, Mühleisen TW, O’Brien N, O’Donovan C, Olde Loohuis LM, Oruc L, Papiol S, Pardiñas AF, Perry A, Pfennig A, Porichi E, Potash JB, Quested D, Raj T, Rapaport MH, DePaulo JR, Regeer EJ, Rice JP, Rivas F, Rivera M, Roth J, Roussos P, Ruderfer DM, Sánchez-Mora C, Schulte EC, Senner F, Sharp S, Shilling PD, Sigurdsson E, Sirignano L, Slaney C, Smeland OB, Smith DJ, Sobell JL, Søholm Hansen C, Soler Artigas M, Spijker AT, Stein DJ, Strauss JS, Świątkowska B, Terao C, Thorgeirsson TE, Toma C, Tooney P, Tsermpini EE, Vawter MP, Vedder H, Walters JT, Witt SH, Xi S, Xu W, Yang JMK, Young AH, Young H, Zandi PP, Zhou H, Zillich L, Adolfsson R, Agartz I, Alda M, Alfredsson L, Babadjanova G, Backlund L, Baune BT, Bellivier F, Bengesser S, Berrettini WH, Blackwood DH, Boehnke M, Børglum AD, Breen G, Carr VJ, Catts S, Corvin A, Craddock N, Dannlowski U, Dikeos D, Esko T, Etain B, Ferentinos P, Frye M, Fullerton JM, Gawlik M, Gershon ES, Goes FS, Green MJ, Grigoroiu-Serbanescu M, Hauser J, Henskens F, Hillert J, Hong KS, Hougaard DM, Hultman CM, Hveem K, Iwata N, Jablensky AV, Jones I, Jones LA, Kahn RS, Kelsoe JR, Kirov G, Landén M, Leboyer M, Lewis CM, Li QS, Lissowska J, Lochner C, Loughland C, Martin NG, Mathews CA, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Melle I, Michie P, Milani L, Mitchell PB, Morken G, Mors O, Mortensen PB, Mowry B, Müller-Myhsok B, Myers RM, Neale BM, Nievergelt CM, Nordentoft M, Nöthen MM, O’Donovan MC, Oedegaard KJ, Olsson T, Owen MJ, Paciga SA, Pantelis C, Pato C, Pato MT, Patrinos GP, Perlis RH, Posthuma D, Ramos-Quiroga JA, Reif A, Reininghaus EZ, Ribasés M, Rietschel M, Ripke S, Rouleau GA, Saito T, Schall U, Schalling M, Schofield PR, Schulze TG, Scott LJ, Scott RJ, Serretti A, Shannon Weickert C, Smoller JW, Stefansson H, Stefansson K, Stordal E, Streit F, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Waldman ID, Weickert TW, Werge T, Wray NR, Zwart JA, Biernacka JM, Nurnberger JI, Cichon S, Edenberg HJ, Stahl EA, McQuillin A, Di Florio A, Ophoff RA, Andreassen OA (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 53

Pages Range: 817-829

Journal Issue: 6

DOI: 10.1038/s41588-021-00857-4

Abstract

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.

Involved external institutions

Karolinska Institute Sweden (SE) Universitätsklinikum Bonn Germany (DE) Universidad Autónoma de Nuevo León Mexico (MX) Ruprecht-Karls-Universität Heidelberg Germany (DE) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Cardiff University United Kingdom (GB) Icahn School of Medicine at Mount Sinai United States (USA) (US) The Jane and Terry Semel Institute for Neuroscience and Human Behavior United States (USA) (US) Institut Mondor de Recherche Biomédicale France (FR) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Landspítali / National University Hospital of Iceland Iceland (IS) Eberhard Karls Universität Tübingen Germany (DE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Emory University United States (USA) (US) Johns Hopkins Hospital United States (USA) (US) Altrecht Netherlands (NL) Washington University in St. Louis United States (USA) (US) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) University of Tokyo Japan (JP) University College London (UCL) United Kingdom (GB) Centre for Addiction and Mental Health (CAMH) Canada (CA) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) HudsonAlpha United States (USA) (US) Medizinische Universität Graz Austria (AT) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Dalhousie University Canada (CA) University of Pennsylvania (UPenn) United States (USA) (US) Lundbeck Foundation Initiative for Integrative Psychiatric Research Denmark (DK) University of Sarajevo Bosnia And Herzegovina (BA) University of Edinburgh United Kingdom (GB) deCODE genetics Iceland (IS) Charité - Universitätsmedizin Berlin Germany (DE) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) King’s College London United Kingdom (GB) University of Queensland Australia (AU) Sungkyunkwan University (SKKU) Korea, Republic of (KR) Aarhus University Denmark (DK) SUNY Downstate Medical Center United States (USA) (US) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Veterans Health Administration (VHA) United States (USA) (US) IMS RIKEN Center for Integrative Medical Sciences Japan (JP) Erasmus University Medical Center (MC) Netherlands (NL) University of Glasgow United Kingdom (GB) PsyQ Netherlands (NL) North East London NHS Foundation Trust United Kingdom (GB) Janssen Global Services, LLC United States (USA) (US) Universitätsklinikum Köln Germany (DE) University of Cape Town (UCT) South Africa (ZA) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Nofer Institute of Occupational Medicine (NIOM) Poland (PL) Korea University / 고려대학교 Korea, Republic of (KR) Massachusetts General Hospital United States (USA) (US) University of Stellenbosch / Universiteit van Stellenbosch South Africa (ZA) University of Newcastle (UoN) Australia (AU) Neuroscience Research Australia NeuRA Australia (AU) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Patras (UPATRAS) Greece (GR) University of Florida United States (USA) (US) University of California Irvine United States (USA) (US) University of Toronto Canada (CA) University of Michigan United States (USA) (US) Pfizer, Inc. United States (USA) (US) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) Mayo Clinic United States (USA) (US) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Pirogov Russian National Research Medical University (RSMU / RNRMU) Russian Federation (RU) University of New South Wales (UNSW) Australia (AU) Harvard University United States (USA) (US) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Montreal Neurological Institute and Hospital (MNI, The Neuro) Canada (CA) Fujita Health University Japan (JP) University of Bologna / Università di Bologna Italy (IT) Namsos Hospital Norway (NO) University of Oslo Norway (NO) Indiana University – Purdue University Indianapolis United States (USA) (US) University of Tartu Estonia (EE) Mario Negri Institute for Pharmacological Research (IRCCS) / Istituto di Ricerche Farmacologiche Mario Negri Italy (IT) University of Chicago United States (USA) (US) National and Kapodistrian University of Athens Greece (GR) Diakonhjemmet Hospital Norway (NO) University Of Worcester United Kingdom (GB) Instituto de Salud Global de Barcelona (ISGlobal) Spain (ES) McGill University Canada (CA) University of California San Francisco (UCSF) United States (USA) (US) University of Missouri-Columbia (Mizzou) United States (USA) (US) Lindner Center of HOPE United States (USA) (US) National Institute of Mental Health Information Resource Center United States (USA) (US) Yale University United States (USA) (US) Umeå University Sweden (SE) University of Galway (NUIG) / Ollscoil na Gaillimhe Ireland (IE) Forschungszentrum Jülich / Research Centre Jülich (FZJ) Germany (DE) University of Southern California (USC) United States (USA) (US) Trinity College Dublin Ireland (IE) Psychiatrisches Krankenhaus Rickling Germany (DE) Universität Münster (ehem. Westfälische Wilhelms-Universität (WWU)) Germany (DE) Université Paris-Sud France (FR) Eginition Hospital Greece (GR) University of Western Australia (UWA) Australia (AU) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Queen Mary University of London United Kingdom (GB) Newcastle University United Kingdom (GB) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Federal State Budget Scientific Institution Research Center of Neurology Russian Federation (RU) Berkshire Healthcare NHS Foundation Trust United Kingdom (GB) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Universidad de Granada Spain (ES) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Universitätsklinikum Würzburg Germany (DE) Vanderbilt University United States (USA) (US) The University of Melbourne Australia (AU)

How to cite

APA:

Mullins, N., Forstner, A.J., O’Connell, K.S., Coombes, B., Coleman, J.R., Qiao, Z.,... Andreassen, O.A. (2021). Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nature Genetics, 53(6), 817-829. https://doi.org/10.1038/s41588-021-00857-4

MLA:

Mullins, Niamh, et al. "Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology." Nature Genetics 53.6 (2021): 817-829.

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