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 Basel), Andrew McQuillin(University College London), Stephan Ripke(Broad Institute), Vassily Trubetskoy, Manuel Mattheisen(Aarhus University), Yunpeng Wang(University of Oslo), Jonathan R. I. Coleman(King's College London), Helena 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), Tune H. Pers(Broad Institute), Peter Holmans(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, 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(ID Genomics (United States)), 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, 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, 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(Institute of Human Genetics), 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(ID Genomics (United States)), Diane Gage(Broad Institute), Julie Garnham, 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(Peninsula College of Medicine and Dentistry), Melissa J. Green(UNSW Sydney), Tiffany A. Greenwood(University of California San Diego), Jakob Grove(Aarhus University), Weihua Guan(University of Minnesota System), JoséGuzman Parra(Instituto de Investigación Biomédica de Málaga), Marian L. Hamshere(Cardiff University), Martin Hautzinger, Urs Heilbronner(ID Genomics (United States)), Stefan Herms(University of Basel), Maria Hipolito(Howard University Hospital), Per Hoffmann(University of Basel), 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(University of Toronto), Sarah Kittel‐Schneider(Goethe University Frankfurt), Sarah Knott(University of Worcester), James A. Knowles(SUNY Downstate Health Sciences University), Manolis Kogevinas(Center for Research in Environmental Epidemiology), Anna C. Koller(Institute of Human Genetics), Ralph Kupka(GGZ inGeest), Catharina Lavebratt(Karolinska University Hospital), Jacob Lawrence(North East London NHS Foundation Trust), William Lawson(Howard University Hospital), Markus Leber(University Hospital Cologne), 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(Institute of Human Genetics), Donald J. MacIntyre(NHS Greater Glasgow and Clyde), 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(National Academy of Medicine), 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, 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, 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(Addiction Research Foundation), 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(3M (United States)), 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(National Institute of Mental Health), Lena Backlund(Karolinska University Hospital), Bernhard T. Baune(The University of Adelaide), 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, 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), RenéS 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(Institute of Human Genetics), 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, 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)), Kari Stefansson(deCODE Genetics (Iceland)), Eystein Stordal(Norwegian University of Science and Technology), Patrick F. Sullivan(University of North Carolina at Chapel Hill), Gustavo Turecki, Arne E Vaaler(St Olav's University Hospital), Eduard Vieta(Centro de Investigación Biomédica en Red de Salud Mental), John B. Vincent(Addiction Research Foundation), Thomas Werge(University of Copenhagen), John I. Nürnberger(University School), Naomi R. Wray(The University of Queensland), Arianna Di Florio(University of North Carolina at Chapel Hill), Howard J. Edenberg(University School), Sven Cichon(National Academy of Medicine), 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(Icahn School of Medicine at Mount Sinai)
Cited by 255Open Access
Abstract
ABSTRACT Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P<1×10 -4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters ( CACNA1C , GRIN2A , SCN2A , SLC4A1 ), synaptic components ( RIMS1 , ANK3 ), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~ 73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~ 17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.
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