Genome-wide association study identifies 30 loci associated with bipolar disorder
Eli A. Stahl(Broad Institute), Gerome Breen(King's College London), Andreas J. Forstner(University of Bonn), Andrew McQuillin(University College London), Stephan Ripke(Broad Institute), Vassily Trubetskoy(Charité - Universitätsmedizin Berlin), Manuel Mattheisen(Aarhus University), Yunpeng Wang(University of Oslo), Jonathan R. I. Coleman(King's College London), Héléna A. Gaspar(King's College London), Christiaan de Leeuw(Amsterdam Neuroscience), Stacy Steinberg(deCODE Genetics (Iceland)), Jennifer M. Whitehead Pavlides(The University of Queensland), Maciej Trzaskowski(The University of Queensland), Enda M. Byrne(The University of Queensland), Tune H. Pers(Broad Institute), Peter Holmans(Cardiff University), Alexander Richards(Cardiff University), Liam Abbott(Broad Institute), Esben Agerbo(Aarhus University), Huda Akil(University of Michigan), Diego Albani(Mario Negri Institute for Pharmacological Research), Ney Alliey‐Rodriguez(University of Chicago), Thomas D. Als(Aarhus University), Adebayo Anjorin(Berkshire Healthcare NHS Foundation Trust), Verneri Antilla(Massachusetts General Hospital), Swapnil Awasthi(Charité - Universitätsmedizin Berlin), Judith A. Badner(Rush University Medical Center), Marie Bækvad‐Hansen(Statens Serum Institut), Jack D. Barchas(Cornell University), Nicholas Bass(University College London), Michael Bauer(University Hospital Carl Gustav Carus), Richard A. Belliveau(Broad Institute), Sarah E. Bergen(Karolinska Institutet), Carsten Bøcker Pedersen(Aarhus University), Erlend Bøen(Diakonhjemmet Hospital), Marco P. Boks(University Medical Center Utrecht), James Boocock(University of California, Los Angeles), Monika Budde(Ludwig-Maximilians-Universität München), William E. Bunney(University of California, Irvine), Margit Burmeister(University of Michigan), Jonas Bybjerg‐Grauholm(Statens Serum Institut), William Byerley(University of California, San Francisco), Miguel Casas(Universitat Autònoma de Barcelona), Felecia Cerrato(Broad Institute), Pablo Cervantes(McGill University Health Centre), Kimberly Chambert(Broad Institute), Alexander W. Charney(Icahn School of Medicine at Mount Sinai), Danfeng Chen(Broad Institute), Claire Churchhouse(Broad Institute), Toni‐Kim Clarke(University of Edinburgh), William Coryell(University of Iowa Hospitals and Clinics), David W. Craig(Translational Genomics Research Institute), Cristiana Cruceanu(McGill University Health Centre), David Curtis(Queen Mary University of London), Piotr M. Czerski(Poznan University of Medical Sciences), Anders M. Dale(University of California San Diego), Simone de Jong(King's College London), Franziska Degenhardt(University of Bonn), Jurgen Del‐Favero(University of Antwerp), J. Raymond DePaulo(Johns Hopkins University), Srdjan Djurovic(Oslo University Hospital), Amanda Dobbyn(Icahn School of Medicine at Mount Sinai), Ashley Dumont(Broad Institute), Torbjørn Elvsåshagen(Oslo University Hospital), Valentina Escott‐Price(Cardiff University), Chun Chieh Fan(University of California San Diego), Sascha B. Fischer(University of Basel), Matthew Flickinger(University of Michigan), Tatiana Foroud(Indiana University – Purdue University Indianapolis), Liz Forty(Cardiff University), Josef Frank(Heidelberg University), Christine Fraser(Cardiff University), Nelson B. Freimer(University of California, Los Angeles), Louise Frisén(Karolinska University Hospital), Katrin Gade(Universitätsmedizin Göttingen), Diane Gage(Broad Institute), Julie Garnham(Dalhousie University), Claudia Giambartolomei(University of California, Los Angeles), Marianne Giørtz Pedersen(Aarhus University), Jaqueline Goldstein(Broad Institute), Scott D. Gordon(QIMR Berghofer Medical Research Institute), Katherine Gordon‐Smith(University of Worcester), Elaine Green(University of Plymouth), Melissa J. Green(UNSW Sydney), Tiffany A. Greenwood(University of California San Diego), Jakob Grove(Aarhus University), Weihua Guan(University of Minnesota System), José Guzmán‐Parra(Instituto de Investigación Biomédica de Málaga), Marian L. Hamshere(Cardiff University), Martin Hautzinger(University of Tübingen), Urs Heilbronner(Ludwig-Maximilians-Universität München), Stefan Herms(University of Bonn), Maria Hipolito(Howard University Hospital), Per Hoffmann(University of Bonn), Dominic Holland(University of California San Diego), Laura M. Huckins(Icahn School of Medicine at Mount Sinai), Stéphane Jamain(Inserm), Jessica Johnson(Icahn School of Medicine at Mount Sinai), Anders Juréus(Karolinska Institutet), Radhika Kandaswamy(King's College London), Robert Karlsson(Karolinska Institutet), 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), Anna C. Koller(University of Bonn), Ralph Kupka(GGZ inGeest), Catharina Lavebratt(Karolinska University Hospital), Jacob Lawrence(East London NHS Foundation Trust), William Lawson(Howard University Hospital), Markus Leber(University Hospital Bonn), Phil H. Lee(Broad Institute), Shawn Levy(HudsonAlpha Institute for Biotechnology), Jun Z. Li(University of Michigan), Chunyu Liu(University of Illinois Chicago), Susanne Lucae(Max Planck Institute of Psychiatry), Anna Maaser(University of Bonn), Donald J. MacIntyre(University of Edinburgh), Pamela B. Mahon(Brigham and Women's Hospital), Wolfgang Maier(University of Bonn), Lina Martinsson(Karolinska University Hospital), Steve McCarroll(Broad Institute), Peter McGuffin(King's College London), Melvin G. McInnis(University of Michigan), James McKay(Centre international de recherche sur le cancer), Helena Medeiros(SUNY Downstate Health Sciences University), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Fan Meng(University of Michigan), Lili Milani(University of Tartu), Grant W. Montgomery(The University of Queensland), Derek W. Morris(Ollscoil na Gaillimhe – University of Galway), Thomas W. Mühleisen(Forschungszentrum Jülich), Niamh Mullins(King's College London), Hoang Nguyen(Icahn School of Medicine at Mount Sinai), Caroline M. Nievergelt(University of California San Diego), Annelie Nordin Adolfsson(Umeå University), Evaristus Nwulia(Howard University Hospital), Claire O’Donovan(Dalhousie University), Loes M. Olde Loohuis(University of California, Los Angeles), Anil P. S. Ori(University of California, Los Angeles), Lilijana Oruč(University of Sarajevo), Urban Ösby(Karolinska University Hospital), Roy H. Perlis(Harvard University), Amy Perry(University of Worcester), Andrea Pfennig(University Hospital Carl Gustav Carus), James B. Potash(Johns Hopkins University), Shaun Purcell(Brigham and Women's Hospital), Eline J. Regeer(Altrecht GGZ), Andreas Reif(Goethe University Frankfurt), Céline S. Reinbold(University of Basel), John P. Rice(Washington University in St. Louis), Fabio Rivas(Instituto de Investigación Biomédica de Málaga), Margarita Rivera(Universidad de Granada), Panos Roussos(Icahn School of Medicine at Mount Sinai), Douglas M. Ruderfer(Vanderbilt University Medical Center), Euijung Ryu(Mayo Clinic in Florida), Cristina Sánchez‐Mora(Universitat Autònoma de Barcelona), Alan F. Schatzberg(Stanford University), William A. Scheftner(Rush University Medical Center), Nicholas J. Schork(Scripps Research Institute), Cynthia Shannon Weickert(UNSW Sydney), Tatyana Shehktman(University of California San Diego), Paul D. Shilling(University of California San Diego), Engilbert Sigurðsson(University of Iceland), Claire Slaney(Dalhousie University), Olav B. Smeland(Oslo University Hospital), Janet L. Sobell(University of Southern California), Christine Søholm Hansen(Statens Serum Institut), Anne T. Spijker(PsyQ), David St Clair(University of Aberdeen), Michael Steffens(Federal Institute for Drugs and Medical Devices), John S. Strauss(Centre for Addiction and Mental Health), Fabian Streit(Heidelberg University), Jana Strohmaier(Heidelberg University), Szabolcs Szelinger(Translational Genomics Research Institute), Robert C. Thompson(University of Michigan), Thorgeir E. Thorgeirsson(deCODE Genetics (Iceland)), Jens Treutlein(Heidelberg University), Helmut Vedder, Weiqing Wang(Icahn School of Medicine at Mount Sinai), Stanley J. Watson(University of Michigan), Thomas W. Weickert(UNSW Sydney), Stephanie H. Witt(Heidelberg University), Simon Xi(Pfizer (United States)), Wei Xu(University of Toronto), Allan H. Young(King's College London), Peter P. Zandi(Johns Hopkins University), Peng Zhang(Johns Hopkins University), Sebastian Zöllner(University of Michigan), Rolf Adolfsson(Umeå University), Ingrid Agartz(University of Oslo), Martin Alda(Dalhousie University), Lena Backlund(Karolinska University Hospital), Bernhard T. Baune(The University of Melbourne), Frank Bellivier(Inserm), Wade H. Berrettini(University of Pennsylvania), Joanna M. Biernacka(Mayo Clinic in Florida), Douglas Blackwood(University of Edinburgh), Michael Boehnke(University of Michigan), Anders D. Børglum(Aarhus University), Aiden Corvin(Trinity College Dublin), Nicholas Craddock(Cardiff University), Mark J. Daly(Broad Institute), Udo Dannlowski(University of Münster), Tõnu Esko(Broad Institute), Bruno Étain(Inserm), Mark A. Frye(Mayo Clinic), Janice M. Fullerton(UNSW Sydney), Elliot S. Gershon(University of Chicago), Michael Gill(Trinity College Dublin), Fernando S. Goes(Johns Hopkins University), Maria Grigoroiu‐Serbânescu(Spitalul Clinic de Psihiatrie Alexandru Obregia), Joanna Hauser(Poznan University of Medical Sciences), David M. Hougaard(Statens Serum Institut), Christina M. Hultman(Karolinska Institutet), Ian Jones(Cardiff University), Lisa Jones(University of Worcester), René S. Kahn(University Medical Center Utrecht), George Kirov(Cardiff University), Mikael Landén(Karolinska Institutet), Marion Leboyer(Inserm), Cathryn M. Lewis(King's College London), Qingqin S. Li(Janssen (United States)), Jolanta Lissowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Nicholas G. Martin(The University of Queensland), Fermín Mayoral(Instituto de Investigación Biomédica de Málaga), Susan L. McElroy(Lindner Center of HOPE), Andrew M. McIntosh(University of Edinburgh), Francis J. McMahon(National Institute of Mental Health), Ingrid Melle(Oslo University Hospital), Andres Metspalu(University of Tartu), Philip B. Mitchell(UNSW Sydney), Gunnar Morken(Norwegian University of Science and Technology), Ole Mors(Aarhus University Hospital), Preben Bo Mortensen(Aarhus University), Bertram Müller‐Myhsok(University of Liverpool), R Myers(HudsonAlpha Institute for Biotechnology), Benjamin M. Neale(Broad Institute), Vishwajit L. Nimgaonkar(University of Pittsburgh), Merete Nordentoft(University of Copenhagen), Markus M. Nöthen(University of Bonn), Michael O‘Donovan(Cardiff University), Ketil J. Øedegaard(Haukeland University Hospital), Michael J. Owen(Cardiff University), Sara A. Paciga(Pfizer (United States)), Carlos N. Pato(SUNY Downstate Health Sciences University), Michele T. Pato(SUNY Downstate Health Sciences University), Daniëlle Posthuma(Amsterdam Neuroscience), Josep Antoni Ramos‐Quiroga(Universitat Autònoma de Barcelona), Marta Ribasés(Universitat Autònoma de Barcelona), Marcella Rietschel(Heidelberg University), Guy A. Rouleau(Montreal Neurological Institute and Hospital), Martin Schalling(Karolinska University Hospital), Peter R. Schofield(UNSW Sydney), Thomas G. Schulze(Johns Hopkins University), Alessandro Serretti(University of Bologna), Jordan W. Smoller(Broad Institute), Hreinn Stefánsson(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Eystein Stordal(Norwegian University of Science and Technology), Patrick F. Sullivan(University of North Carolina at Chapel Hill), Gustavo Turecki(McGill University), Arne E. Vaaler(St Olav's University Hospital), Eduard Vieta(Centro de Investigación Biomédica en Red de Salud Mental), John B. Vincent(Centre for Addiction and Mental Health), Thomas Werge(University of Copenhagen), John I. Nürnberger(Indiana University School of Medicine), Naomi R. Wray(The University of Queensland), Arianna Di Florio(University of North Carolina at Chapel Hill), Howard J. Edenberg(Indiana University School of Medicine), Sven Cichon(University of Bonn), Roel A. Ophoff(University of California, Los Angeles), Laura J. Scott(University of Michigan), Ole A. Andreassen(Oslo University Hospital), John R. Kelsoe(University of California San Diego), Pamela Sklar(Johns Hopkins University)
Cited by 1,622Open Access
Abstract
) 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.
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