Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

• DOI: 10.1101/173062
• Publication Date: 2017-08-08T14:09:37Z
• Authors: Eli A Stahl; Gerome Breen; Andreas J Forstner; Andrew McQuillin; Stephan Ripke; Vassily Trubetskoy; Manuel Mattheisen; Yunpeng Wang; Jonathan R I Coleman; Héléna A Gaspar; Christiaan A de L...; Stacy Steinberg; Jennifer M Whiteh...; Maciej Trzaskowski; Tune H Pers; Peter A Holmans; Liam Abbott; Esben Agerbo; Huda Akil; Diego Albani; Ney Alliey-Rodriguez; Thomas D Als; Adebayo Anjorin; Verneri Antilla; Swapnil Awasthi; Judith A Badner; Marie Bækvad-Hansen; Jack D Barchas; Nicholas Bass; Michael Bauer; Richard Belliveau; Sarah E Bergen; Carsten Bøcker Pe...; Erlend Bøen; Marco Boks; James Boocock; Monika Budde; William Bunney; Margit Burmeister; Jonas Bybjerg-Gra...; William Byerley; Miquel Casas; Felecia Cerrato; Pablo Cervantes; Kimberly Chambert; Alexander W Charney; Danfeng Chen; Claire Churchhouse; Toni-Kim Clarke; William Coryell; David W Craig; Cristiana Cruceanu; David Curtis; Piotr M Czerski; Anders M Dale; Simone de Jong; Franziska Degenhardt; Jurgen Del-Favero; J Raymond DePaulo; Srdjan Djurovic; Amanda L Dobbyn; Ashley Dumont; Torbjørn Elvsåshagen; Valentina Escott-...; Chun Chieh Fan; Sascha B Fischer; Matthew Flickinger; Tatiana M Foroud; Liz Forty; Josef Frank; Christine Fraser; Nelson B Freimer; Louise Frisén; Katrin Gade; Diane Gage; Julie Garnham; Claudia Giambarto...; Marianne Giørtz P...; Jaqueline Goldstein; Scott D Gordon; Katherine Gordon-...; Elaine K Green; Melissa J Green; Tiffany A Greenwood; Jakob Grove; Weihua Guan; JoséGuzman Parra; Marian L Hamshere; Martin Hautzinger; Urs Heilbronner; Stefan Herms; Maria Hipolito; Per Hoffmann; Dominic Holland; Laura Huckins; Stéphane Jamain; Jessica S Johnson; Anders Juréus; Radhika Kandaswamy; Robert Karlsson; James L Kennedy; Sarah Kittel-Schn...; Sarah V Knott; James A Knowles; Manolis Kogevinas; Anna C Koller; Ralph Kupka; Catharina Lavebratt; Jacob Lawrence; William B Lawson; Markus Leber; Phil H Lee; Shawn E Levy; Jun Z Li; Chunyu Liu; Susanne Lucae; Anna Maaser; Donald J MacIntyre; Pamela B Mahon; Wolfgang Maier; Lina Martinsson; Steve McCarroll; Peter McGuffin; Melvin G McInnis; James D McKay; Helena Medeiros; Sarah E Medland; Fan Meng; Lili Milani; Grant W Montgomery; Derek W Morris; Thomas W Mühleisen; Niamh Mullins; Hoang Nguyen; Caroline M Niever...; Annelie Nordin Ad...; Evaristus A Nwulia; Claire O’Donovan; Loes M Olde Loohuis; Anil P S Ori; Lilijana Oruc; Urban Ösby; Roy H Perlis; Amy Perry; Andrea Pfennig; James B Potash; Shaun M Purcell; Eline J Regeer; Andreas Reif; Céline S Reinbold; John P Rice; Fabio Rivas; Margarita Rivera; Panos Roussos; Douglas M Ruderfer; Euijung Ryu; Cristina Sánchez-...; Alan F Schatzberg; William A Scheftner; Nicholas J Schork; Cynthia Shannon W...; Tatyana Shehktman; Paul D Shilling; Engilbert Sigurdsson; Claire Slaney; Olav B Smeland; Janet L Sobell; Christine Søholm ...; Anne T Spijker; David St Clair; Michael Steffens; John S Strauss; Fabian Streit; Jana Strohmaier; Szabolcs Szelinger; Robert C Thompson; Thorgeir E Thorge...; Jens Treutlein; Helmut Vedder; Weiqing Wang; Stanley J Watson; Thomas W Weickert; Stephanie H Witt; Simon Xi; Wei Xu; Allan H Young; Peter Zandi; Peng Zhang; Sebastian Zollner; Rolf Adolfsson; Ingrid Agartz; Martin Alda; Lena Backlund; Bernhard T Baune; Frank Bellivier; Wade H Berrettini; Joanna M Biernacka; Douglas H R Black...; Michael Boehnke; Anders D Børglum; Aiden Corvin; Nicholas Craddock; Mark J Daly; Udo Dannlowski; Tõnu Esko; Bruno Etain; Mark Frye; Janice M Fullerton; Elliot S Gershon; Michael Gill; Fernando Goes; Maria Grigoroiu-S...; Joanna Hauser; David M Hougaard; Christina M Hultman; Ian Jones; Lisa A Jones; RenéS Kahn; George Kirov; Mikael Landén; Marion Leboyer; Cathryn M Lewis; Qingqin S Li; Jolanta Lissowska; Nicholas G Martin; Fermin Mayoral; Susan L McElroy; Andrew M McIntosh; Francis J McMahon; Ingrid Melle; Andres Metspalu; Philip B Mitchell; Gunnar Morken; Ole Mors; Preben Bo Mortensen; Bertram Müller-My...; Richard M Myers; Benjamin M Neale; Vishwajit Nimgaonkar; Merete Nordentoft; Markus M Nöthen; Michael C O’Donovan; Ketil J Oedegaard; Michael J Owen; Sara A Paciga; Carlos Pato; Michele T Pato; Danielle Posthuma; Josep Antoni Ramo...; Marta Ribasés; Marcella Rietschel; Guy A Rouleau; Martin Schalling; Peter R Schofield; Thomas G Schulze; Alessandro Serretti; Jordan W Smoller; Hreinn Stefansson; Kari Stefansson; Eystein Stordal; Patrick F Sullivan; Gustavo Turecki; Arne E Vaaler; Eduard Vieta; John B Vincent; Thomas Werge; John I Nurnberger; Naomi R Wray; Arianna Di Florio; Howard J Edenberg; Sven Cichon; Roel A Ophoff; Laura J Scott; Ole A Andreassen; John Kelsoe; Pamela Sklar
• Keywords: Male; 0301 basic medicine; Schizophrenia/genetics; Bipolar Disorder; LD SCORE REGRESSION; VARIANTS; Medical and Health Sciences; SCHIZOPHRENIA; GWAS; 2.1 Biological and endogenous factors; Bipolar Disorder; Case-Control Studies; Depressive Disorder, Major; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Male; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia; Systems Biology; Genetic Loci; anzsrc-for: 31 Biological Sciences; Psychotic Disorders/genetics; eQTLGen Consortium; RISK; 0303 health sciences; HERITABILITY; Systems Biology; Variants; Major/genetics; Single Nucleotide; Metaanalysis; Biological Sciences; Serious Mental Illness; Mental Illness; Bioinformatics and computational biology; 3. Good health; [SDV] Life Sciences [q-bio]; Mental Health; Mental health; Female; BIOS Consortium; Depressive Disorder, Major/genetics; Gwas; Biotechnology; Risk; 570; GENES; 572; 1.1 Normal biological development and functioning; Agricultural biotechnology; 610; Polymorphism, Single Nucleotide; 3105 Genetics; Bipolar Disorder/classification; Article; Heritability; anzsrc-for: 3102 Bioinformatics and computational biology; 03 medical and health sciences; 1311 Genetics; SDG 3 - Good Health and Well-being; anzsrc-for: 3001 Agricultural biotechnology; Polygenicity; 616; Genetics; POLYGENICITY; Humans; Genetic Predisposition to Disease; Polymorphism; METAANALYSIS; Depressive Disorder; Depressive Disorder, Major; Ld Score Regression; Human Genome; Individuals; Major; Bipolar Disorder Working Group of the Psychiatric Genomics Consortium; Brain Disorders; anzsrc-for: 3105 Genetics; INDIVIDUALS; anzsrc-for: 11 Medical and Health Sciences; Genes; Psychotic Disorders; Genetic Loci; Case-Control Studies; anzsrc-for: 06 Biological Sciences; Schizophrenia; Human medicine; 31 Biological Sciences; Developmental Biology; Genome-Wide Association Study

ABSTRACTBipolar 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.