Genome-wide association study identifies 30 loci associated with bipolar disorder

Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V, Mattheisen M, Wang Y, Coleman JR, Gaspar HA, de Leeuw CA, Steinberg S, Pavlides JM, Trzaskowski M, Byrne EM, Pers TH, Holmans PA, Richards AL, Abbott L, Agerbo E, Akil H, Albani D, Alliey-Rodriguez N, Als TD, Anjorin A, Antilla V, Awasthi S, Badner JA, Bækvad-Hansen M, Barchas JD, Bass N, Bauer M, Belliveau R, Bergen SE, Pedersen CB, Bøen E, Boks MP, Boocock J, Budde M, Bunney W, Burmeister M, Bybjerg-Grauholm J, Byerley W, Casas M, Cerrato F, Cervantes P, Chambert K, Charney AW, Chen D, Churchhouse C, Clarke TK, Coryell W, Craig DW, Cruceanu C, Curtis D, Czerski PM, Dale AM, de Jong S, Degenhardt F, Del-Favero J, DePaulo JR, Djurovic S, Dobbyn AL, Dumont A, Elvsåshagen T, Escott-Price V, Fan CC, Fischer SB, Flickinger M, Foroud TM, Forty L, Frank J, Fraser C, Freimer NB, Frisén L, Gade K, Gage D, Garnham J, Giambartolomei C, Pedersen MG, Goldstein J, Gordon SD, Gordon-Smith K, Green EK, Green MJ, Greenwood TA, Grove J, Guan W, Guzman-Parra J, Hamshere ML, Hautzinger M, Heilbronner U, Herms S, Hipolito M, Hoffmann P, Holland D, Huckins L, Jamain S, Johnson JS, Juréus A, Kandaswamy R, Karlsson R, Kennedy JL, Kittel-Schneider S, Knowles JA, Kogevinas M, Koller AC, Kupka R, Lavebratt C, Lawrence J, Lawson WB, Leber M, Lee PH, Levy SE, Li JZ, Liu C, Lucae S, Maaser A, MacIntyre DJ, Mahon PB, Maier W, Martinsson L, McCarroll S, McGuffin P, McInnis MG, McKay JD, Medeiros H, Medland SE, Meng F, Milani L, Montgomery GW, Morris DW, Mühleisen TW, Mullins N, Nguyen H, Nievergelt CM, Adolfsson AN, Nwulia EA, O’Donovan C, Loohuis LM, Ori AP, Oruc L, Ösby U, Perlis RH, Perry A, Pfennig A, Potash JB, Purcell SM, Regeer EJ, Reif A, Reinbold CS, Rice JP, Rivas F, Rivera M, Roussos P, Ruderfer DM, Ryu E, Sánchez-Mora C, Schatzberg AF, Scheftner WA, Schork NJ, Shannon Weickert C, Shehktman T, Shilling PD, Sigurdsson E, Slaney C, Smeland OB, Sobell JL, Søholm Hansen C, Spijker AT, St Clair D, Steffens M, Strauss JS, Streit F, Strohmaier J, Szelinger S, Thompson RC, Thorgeirsson TE, Treutlein J, Vedder H, Wang W, Watson SJ, Weickert TW, Witt SH, Xi S, Xu W, Young AH, Zandi P, Zhang P, Zöllner S, Adolfsson R, Agartz I, Alda M, Backlund L, Baune BT, Bellivier F, Berrettini WH, Biernacka JM, Blackwood DH, Boehnke M, Børglum AD, Corvin A, Craddock N, Daly MJ, Dannlowski U, Esko T, Etain B, Frye M, Fullerton JM, Gershon ES, Gill M, Goes F, Grigoroiu-Serbanescu M, Hauser J, Hougaard DM, Hultman CM, Jones I, Jones LA, Kahn RS, Kirov G, Landén M, Leboyer M, Lewis CM, Li QS, Lissowska J, Martin NG, Mayoral F, McElroy SL, McIntosh AM, McMahon FJ, Melle I, Metspalu A, Mitchell PB, Morken G, Mors O, Mortensen PB, Müller-Myhsok B, Myers RM, Neale BM, Nimgaonkar V, Nordentoft M, Nöthen MM, O’Donovan MC, Oedegaard KJ, Owen MJ, Paciga SA, Pato C, Pato MT, Posthuma D, Ramos-Quiroga JA, Ribasés M, Rietschel M, Rouleau GA, Schalling M, Schofield PR, Schulze TG, Serretti A, Smoller JW, Stefansson H, Stefansson K, Stordal E, Sullivan PF, Turecki G, Vaaler AE, Vieta E, Vincent JB, Werge T, Nurnberger JI, Wray NR, Di Florio A, Edenberg HJ, Cichon S, Ophoff RA, Scott LJ, Andreassen OA, Kelsoe J, Sklar P (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 51

Pages Range: 793-803

Journal Issue: 5

DOI: 10.1038/s41588-019-0397-8

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 ⁻⁴ in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 ⁻⁸ ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Involved external institutions

University of Michigan United States (USA) (US) Dalhousie University Canada (CA) Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) Spain (ES) Diakonhjemmet Hospital Norway (NO) Icahn School of Medicine at Mount Sinai United States (USA) (US) Klinikum der Universität München (LMU Klinikum) Germany (DE) Universität Basel Switzerland (CH) University College London (UCL) United Kingdom (GB) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Charité - Universitätsmedizin Berlin Germany (DE) Weill Cornell Medicine United States (USA) (US) Institute of Biological Psychiatry Denmark (DK) Medical Research Council United Kingdom (GB) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) deCODE genetics Iceland (IS) Eberhard Karls Universität Tübingen Germany (DE) University of Queensland Australia (AU) Mayo Clinic United States (USA) (US) University of California, San Diego (UC San Diego, UCSD) United States (USA) (US) The Jane and Terry Semel Institute for Neuroscience and Human Behavior United States (USA) (US) Max-Planck-Institut für Psychiatrie (Deutsche Forschungsanstalt für Psychiatrie) Germany (DE) University of Sarajevo Bosnia And Herzegovina (BA) Scripps Research Institute (TSRI) United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Cardiff University United Kingdom (GB) University of California Los Angeles (UCLA) United States (USA) (US) University of California Irvine United States (USA) (US) Stanford University United States (USA) (US) Lundbeck Foundation Initiative for Integrative Psychiatric Research Denmark (DK) Ruprecht-Karls-Universität Heidelberg Germany (DE) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Rush University United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) McGill University Health Centre (MUHC) / Centre universitaire de santé McGill Canada (CA) University of Southern California (USC) United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Peninsula College of Medicine and Dentistry (PCMD) United Kingdom (GB) University of Edinburgh United Kingdom (GB) University of Antwerp / Universiteit Antwerpen Belgium (BE) Johns Hopkins Hospital United States (USA) (US) Oslo University Hospital, Ullevål / Oslo universitetssykehus, Ullevål Norway (NO) HudsonAlpha United States (USA) (US) King’s College London United Kingdom (GB) Karolinska Institute Sweden (SE) Namsos Hospital Norway (NO) University of Galway (NUIG) / Ollscoil na Gaillimhe Ireland (IE) Translational Genomics Research Institute (TGen) United States (USA) (US) Aarhus University Denmark (DK) Queen Mary University of London United Kingdom (GB) University of Tartu Estonia (EE) University of New South Wales (UNSW) Australia (AU) University of Iceland (UI) / Háskóli Íslands Iceland (IS) University of Aberdeen United Kingdom (GB) Johns Hopkins University (JHU) United States (USA) (US) Umeå University Sweden (SE) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) Neuroscience Research Australia NeuRA Australia (AU) Indiana University – Purdue University Indianapolis United States (USA) (US) Centre for Addiction and Mental Health (CAMH) Canada (CA) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) University of Chicago United States (USA) (US) Universitätsklinikum Bonn Germany (DE) Trinity College Dublin Ireland (IE) Howard University Hospital (HUH) / Freedmen's Hospital United States (USA) (US) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) University of Illinois at Chicago United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Instituto de Salud Global de Barcelona (ISGlobal) Spain (ES) East London NHS Foundation Trust United Kingdom (GB) Massachusetts General Hospital United States (USA) (US) Vanderbilt University United States (USA) (US) University of Iowa Hospitals and Clinics (UIHC) United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Poznan University of Medical Sciences / Uniwersytet Medyczny im. Karola Marcinkowskiego w Poznaniu Poland (PL) Pfizer, Inc. United States (USA) (US) Janssen Global Services, LLC United States (USA) (US) McGill University Canada (CA) University of Toronto Canada (CA) Psychiatrisches Krankenhaus Rickling Germany (DE) University of Bologna / Università di Bologna Italy (IT) Princess Margaret Cancer Centre / Princess Margaret Hospital Canada (CA) NTNU Trondheim - Norwegian University of Science and Technology Norway (NO) University of Pennsylvania (UPenn) United States (USA) (US) Mario Negri Institute for Pharmacological Research (IRCCS) / Istituto di Ricerche Farmacologiche Mario Negri Italy (IT) Berkshire Healthcare NHS Foundation Trust United Kingdom (GB) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Lindner Center of HOPE United States (USA) (US) Harvard University United States (USA) (US) University Of Worcester United Kingdom (GB) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Washington University in St. Louis United States (USA) (US) Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) / Federal Institute for Drugs and Medical Devices Germany (DE) Université Paris Cité France (FR) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) National Institute of Mental Health Information Resource Center United States (USA) (US) University of Pittsburgh United States (USA) (US) Institut Mondor de Recherche Biomédicale France (FR) NHS Scotland - Scotland's Health on the Web United Kingdom (GB)

How to cite

APA:

Stahl, E.A., Breen, G., Forstner, A.J., McQuillin, A., Ripke, S., Trubetskoy, V.,... Sklar, P. (2019). Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics, 51(5), 793-803. https://doi.org/10.1038/s41588-019-0397-8

MLA:

Stahl, Eli A., et al. "Genome-wide association study identifies 30 loci associated with bipolar disorder." Nature Genetics 51.5 (2019): 793-803.

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