Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
Niamh Mullins(Icahn School of Medicine at Mount Sinai), Andreas J. Forstner(University of Bonn), Kevin S. O’Connell(Oslo University Hospital), Brandon J. Coombes(Mayo Clinic in Florida), Jonathan R. I. Coleman(King's College London), Zhen Qiao(The University of Queensland), Thomas D. Als(Aarhus University), Tim B. Bigdeli(SUNY Downstate Health Sciences University), Sigrid Børte(Oslo University Hospital), Julien Bryois(Karolinska Institutet), Alexander W. Charney(Icahn School of Medicine at Mount Sinai), Ole Kristian Drange(Norwegian University of Science and Technology), Michael J. Gandal(University of California, Los Angeles), Saskia P. Hagenaars(King's College London), Masashi Ikeda(Fujita Health University), Nolan Kamitaki(Broad Institute), Minsoo Kim(University of California, Los Angeles), Kristi Krebs(University of Tartu), Georgia Panagiotaropoulou(Charité - Universitätsmedizin Berlin), Brian M. Schilder(Icahn School of Medicine at Mount Sinai), Laura Sloofman(Icahn School of Medicine at Mount Sinai), Stacy Steinberg(deCODE Genetics (Iceland)), Vassily Trubetskoy(Charité - Universitätsmedizin Berlin), Bendik S. Winsvold(Oslo University Hospital), Hong‐Hee Won(Samsung Medical Center), Liliya Abramova(Mental Health Research Center of Russian Academy of Medical Sciences), Kristina Adorjan(LMU Klinikum), Esben Agerbo(Aarhus University), Mariam Al Eissa(University College London), Diego Albani(Mario Negri Institute for Pharmacological Research), Ney Alliey‐Rodriguez(Northwestern University), Adebayo Anjorin(Berkshire Healthcare NHS Foundation Trust), Verneri Antilla(Massachusetts General Hospital), Anastasia Antoniou(National and Kapodistrian University of Athens), Swapnil Awasthi(Charité - Universitätsmedizin Berlin), Ji Hyun Baek(Samsung Medical Center), Marie Bækvad‐Hansen(Statens Serum Institut), Nicholas Bass(University College London), Michael Bauer(University Hospital Carl Gustav Carus), Eva C. Beins(University of Bonn), Sarah E. Bergen(Karolinska Institutet), Armin Birner(Medical University of Graz), Carsten Bøcker Pedersen(Aarhus University), Erlend Bøen(Diakonhjemmet Hospital), Marco P. Boks(University Medical Center Utrecht), Rosa Bosch(Universitat Autònoma de Barcelona), Murielle Brum(Goethe University Frankfurt), Ben Brumpton(Norwegian University of Science and Technology), Nathalie Brunkhorst-Kanaan(Goethe University Frankfurt), Monika Budde(Ludwig-Maximilians-Universität München), Jonas Bybjerg‐Grauholm(Statens Serum Institut), William Byerley(University of California, San Francisco), Murray J. Cairns(University of Newcastle Australia), Miguel Casas(Universitat Autònoma de Barcelona), Pablo Cervantes(McGill University Health Centre), Toni‐Kim Clarke(University of Edinburgh), Cristiana Cruceanu(McGill University Health Centre), Alfredo B. Cuéllar‐Barboza(Mayo Clinic), Julie M. Cunningham(Mayo Clinic in Arizona), David Curtis(Queen Mary University of London), Piotr M. Czerski(Poznan University of Medical Sciences), Anders M. Dale(University of California San Diego), Nina Dalkner(Medical University of Graz), Friederike S. David(University of Bonn), Franziska Degenhardt(University of Bonn), Srdjan Djurovic(Oslo University Hospital), Amanda Dobbyn(Icahn School of Medicine at Mount Sinai), Athanassios Douzenis(National and Kapodistrian University of Athens), Torbjørn Elvsåshagen(Oslo University Hospital), Valentina Escott‐Price(Cardiff University), I. Nicol Ferrier(Newcastle University), Alessia Fiorentino(University College London), Tatiana Foroud(Indiana University – Purdue University Indianapolis), Liz Forty(Cardiff University), Josef Frank(Heidelberg University), Oleksandr Frei(Oslo University Hospital), Nelson B. Freimer(University of California, Los Angeles), Louise Frisén(Karolinska Institutet), Katrin Gade(Universitätsmedizin Göttingen), Julie Garnham(Dalhousie University), Joel Gelernter(Yale University), Marianne Giørtz Pedersen(Aarhus 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(Aarhus University), José Guzmán‐Parra(Instituto de Investigación Biomédica de Málaga), Kyooseob Ha(Seoul National University), Magnús Haraldsson(Reykjavík University), Martin Hautzinger(University of Tübingen), Urs Heilbronner(Ludwig-Maximilians-Universität München), Dennis Hellgren(Karolinska Institutet), Stefan Herms(University of Bonn), Per Hoffmann(University of Bonn), Peter Holmans(Cardiff University), Laura M. Huckins(Icahn School of Medicine at Mount Sinai), Stéphane Jamain(Inserm), Jessica Johnson(Icahn School of Medicine at Mount Sinai), János Kálmán(LMU Klinikum), Yoichiro Kamatani(RIKEN Center for Integrative Medical Sciences), James L. Kennedy(Centre for Addiction and Mental Health), Sarah Kittel‐Schneider(Goethe University Frankfurt), James A. Knowles(SUNY Downstate Health Sciences University), Manolis Kogevinas(Barcelona Institute for Global Health), Maria Koromina(University of Patras), Thorsten M. Kranz(Goethe University Frankfurt), Henry R. Kranzler(University of Pennsylvania), Michiaki Kubo(RIKEN Center for Integrative Medical Sciences), Ralph Kupka(GGZ inGeest), Steven A. Kushner(Erasmus MC), Catharina Lavebratt(Karolinska University Hospital), Jacob Lawrence(North East London NHS Foundation Trust), Markus Leber(University Hospital Cologne), Heon‐Jeong Lee(Korea University), Phil H. Lee(Harvard University), Shawn Levy(HudsonAlpha Institute for Biotechnology), Catrin Lewis(King's College London), Calwing Liao(Montreal Neurological Institute and Hospital), Susanne Lucae(Max Planck Institute of Psychiatry), Martin Lundberg(Karolinska University Hospital), Donald J. MacIntyre(University of Edinburgh), Sigurður H. Magnússon(deCODE Genetics (Iceland)), Wolfgang Maier(University of Bonn), Adam X. Maihofer(University of California San Diego), Dolores Malaspina(Icahn School of Medicine at Mount Sinai), Eirini Maratou(National and Kapodistrian University of Athens), Lina Martinsson(Karolinska Institutet), Manuel Mattheisen(Aarhus University), Steven A. McCarroll(Broad Institute), Nathaniel W. McGregor(Stellenbosch University), Peter McGuffin(King's College London), James McKay(Centre international de recherche sur le cancer), Helena Medeiros(SUNY Downstate Health Sciences University), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Vincent Millischer(Karolinska University Hospital), Grant W. Montgomery(The University of Queensland), Jennifer L. Moran(Broad Institute), Derek W. Morris(Ollscoil na Gaillimhe – University of Galway), Thomas W. Mühleisen(Forschungszentrum Jülich), Niamh L. O’Brien(University College London), Claire O’Donovan(Dalhousie University), Loes M. Olde Loohuis(University of California, Los Angeles), Lilijana Oruč(Sarajevo School of Science and Technology), Sergi Papiol(LMU Klinikum), Antonio F. Pardiñas(Cardiff University), Amy Perry(University of Worcester), Andrea Pfennig(University Hospital Carl Gustav Carus), Evgenia Porichi(National and Kapodistrian University of Athens), James B. Potash(Johns Hopkins University), Digby Quested(Oxford Health NHS Foundation Trust), Towfique Raj(Icahn School of Medicine at Mount Sinai), Mark Hyman Rapaport(Emory University), J. Raymond DePaulo(Johns Hopkins University), Eline J. Regeer(Altrecht GGZ), John P. Rice(Washington University in St. Louis), Fabio Rivas(Instituto de Investigación Biomédica de Málaga), Margarita Rivera(Universidad de Granada), Julian Roth(Universitätsklinikum Würzburg), Panos Roussos(Icahn School of Medicine at Mount Sinai), Douglas M. Ruderfer(Vanderbilt University Medical Center), Cristina Sánchez‐Mora(Universitat Autònoma de Barcelona), Eva C. Schulte(LMU Klinikum), Fanny Senner(LMU Klinikum), Sally I. Sharp(University College London), Paul D. Shilling(University of California San Diego), Engilbert Sigurðsson(Reykjavík University), Lea Sirignano(Heidelberg University), Claire Slaney(Dalhousie University), Olav B. Smeland(Oslo University Hospital), Daniel J. Smıth(University of Glasgow), Janet L. Sobell(University of Southern California), Christine Søholm Hansen(Statens Serum Institut), María Soler Artigas(Universitat Autònoma de Barcelona), Anne T. Spijker(PsyQ), Dan J. Stein(South African Medical Research Council), John S. Strauss(Centre for Addiction and Mental Health), Beata Świątkowska(Nofer Institute of Occupational Medicine), Chikashi Terao(RIKEN Center for Integrative Medical Sciences), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Claudio Toma(UNSW Sydney), Paul A. Tooney(University of Newcastle Australia), Evangelia Eirini Tsermpini(University of Patras), Marquis P. Vawter(University of California, Irvine), Helmut Vedder, James Walters(Cardiff University), Stephanie H. Witt(Heidelberg University), Simon Xi(Pfizer (United States)), Wei Xu(University of Toronto), Jessica Yang(Cardiff University), Allan H. Young(King's College London), Hannah Young(Icahn School of Medicine at Mount Sinai), Peter P. Zandi(Johns Hopkins University), Hang Zhou(Yale University), Lea Zillich(Heidelberg University), HUNT All-In Psychiatry(Umeå University), Rolf Adolfsson(Diakonhjemmet Hospital), Ingrid Agartz(Dalhousie University), Martin Alda(Dalhousie University), Lars Alfredsson(Karolinska Institutet), Gulja Babadjanova(Karolinska Institutet), Lena Backlund(Karolinska University Hospital), Bernhard T. Baune(Inserm), Frank Bellivier(Inserm), Susanne Bengesser(Medical University of Graz), Wade H. Berrettini(University of Pennsylvania), Douglas Blackwood(University of Michigan), Michael Boehnke(University of Michigan), Anders D. Børglum(King's College London), Gerome Breen(King's College London), Vaughan J. Carr(The University of Queensland), Stanley V. Catts(The University of Queensland), Aiden Corvin(Trinity College Dublin), Nicholas Craddock(University of Münster), Udo Dannlowski(National and Kapodistrian University of Athens), Dimitris Dikeos(National and Kapodistrian University of Athens), Tõnu Esko(Broad Institute), Bruno Étain(Inserm), Panagiotis Ferentinos(Mayo Clinic), Mark A. Frye(Mayo Clinic), Janice M. Fullerton(UNSW Sydney), Micha Gawlik(University of Chicago), Elliot S. Gershon(Johns Hopkins University), Fernando S. Goes(Johns Hopkins University), Melissa J. Green(UNSW Sydney), Maria Grigoroiu‐Serbânescu(Poznan University of Medical Sciences), Joanna Hauser(Poznan University of Medical Sciences), Frans A. Henskens(Karolinska Institutet), Jan Hillert(Samsung Medical Center), Kyung Sue Hong(Statens Serum Institut), David M. Hougaard(Statens Serum Institut), Christina M. Hultman(Norwegian University of Science and Technology), Kristian Hveem(Fujita Health University), Nakao Iwata(Fujita Health University), Assen Jablensky(The University of Western Australia), Ian Jones(Cardiff University), Lisa Jones(University Medical Center Utrecht), René S. Kahn(University Medical Center Utrecht), John R. Kelsoe(University of California San Diego), George Kirov(Karolinska Institutet), Mikael Landén(Inserm), Marion Leboyer(Inserm), Cathryn M. Lewis(King's College London), Qingqin S. Li(The Maria Sklodowska-Curie National Research Institute of Oncology), Jolanta Lissowska(South African Medical Research Council), Christine Löchner(South African Medical Research Council), Carmel M. Loughland(QIMR Berghofer Medical Research Institute), Nicholas G. Martin(The University of Queensland), Carol A. Mathews(University of Florida), Fermín Mayoral(Lindner Center of HOPE), Susan L. McElroy(Lindner Center of HOPE), Andrew M. McIntosh(National Institute of Mental Health), Francis J. McMahon(University of Oslo), Ingrid Melle(Oslo University Hospital), Patricia T. Michie(University of Tartu), Lili Milani(UNSW Sydney), Philip B. Mitchell(Norwegian University of Science and Technology), Gunnar Morken(Norwegian University of Science and Technology), Ole Mors(Aarhus University), Preben Bo Mortensen(The University of Queensland), Bryan Mowry(The University of Queensland), Bertram Müller‐Myhsok(University of Liverpool), R Myers(Massachusetts General Hospital), Benjamin M. Neale(Broad Institute), Caroline M. Nievergelt(University of California San Diego), Merete Nordentoft(University of Copenhagen), Markus M. Nöthen(University of Bonn), Michael O‘Donovan(Haukeland University Hospital), Ketil J. Øedegaard(Karolinska University Hospital), Tomas Olsson(Karolinska University Hospital), Michael J. Owen(Pfizer (United States)), Sara A. Paciga(The University of Melbourne), Christos Pantelis(The University of Melbourne), Carlos N. Pato(SUNY Downstate Health Sciences University), Michele T. Pato(University of Patras), George P. Patrinos(Harvard University), Roy H. Perlis(Harvard University), Daniëlle Posthuma(Universitat Autònoma de Barcelona), Josep Antoni Ramos‐Quiroga(Goethe University Frankfurt), Andreas Reif(Goethe University Frankfurt), Eva Z. Reininghaus(Universitat Autònoma de Barcelona), Marta Ribasés(Universitat Autònoma de Barcelona), Marcella Rietschel(Heidelberg University), Stephan Ripke(Broad Institute), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Takeo Saito(Fujita Health University), Ulrich Schall(Karolinska Institutet), Martin Schalling(Karolinska University Hospital), Peter R. Schofield(UNSW Sydney), Thomas G. Schulze(Johns Hopkins University), Laura J. Scott(University of Michigan), Rodney J. Scott(University of Newcastle Australia), Alessandro Serretti(Neuroscience Research Australia), Cynthia Shannon Weickert(SUNY Upstate Medical University), Jordan W. Smoller(Broad Institute), Hreinn Stefánsson(deCODE Genetics (Iceland)), Kari Stefansson(deCODE Genetics (Iceland)), Eystein Stordal(Heidelberg University), Fabian Streit(University of North Carolina at Chapel Hill), Patrick F. Sullivan(University of North Carolina at Chapel Hill), Gustavo Turecki(St Olav's University Hospital), Arne E. Vaaler(Centro de Investigación Biomédica en Red de Salud Mental), Eduard Vieta(Centre for Addiction and Mental Health), John B. Vincent(Centre for Addiction and Mental Health), Irwin D. Waldman(Emory University), Thomas W. Weickert(SUNY Upstate Medical University), Thomas Werge(University of Copenhagen), Naomi R. Wray(Oslo University Hospital), John‐Anker Zwart(Oslo University Hospital), Joanna M. Biernacka(Mayo Clinic), John I. Nürnberger(University of Basel), Sven Cichon(University of Bonn), Howard J. Edenberg(Broad Institute), Eli A. Stahl(Broad Institute), Andrew McQuillin(University College London), Arianna Di Florio(University of North Carolina at Chapel Hill), Roel A. Ophoff(University of California, Los Angeles), Ole A. Andreassen(Oslo University Hospital)
Cited by 1,572Open Access
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.
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