Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology
Authors: Mullins Niamh , Forstner Andreas J. , O’Connell Kevin S. , Coombes Brandon , Coleman Jonathan R. I. , Qiao Zhen , Als Thomas D. , Bigdeli Tim B. , Børte Sigrid , Bryois Julien , Charney Alexander W. , Drange Ole Kristian , Gandal Michael J. , Hagenaars Saskia P. , Ikeda Masashi , Kamitaki Nolan , Kim Minsoo , Krebs Kristi , Panagiotaropoulou Georgia , Schilder Brian M. , Sloofman Laura G. , Steinberg Stacy , Trubetskoy Vassily , Winsvold Bendik S. , Won Hong-Hee , Abramova Liliya , Adorjan Kristina , Agerbo Esben , Al Eissa Mariam , Albani Diego , Alliey-Rodriguez Ney , Anjorin Adebayo , Antilla Verneri , Antoniou Anastasia , Awasthi Swapnil , Baek Ji Hyun , Bækvad-Hansen Marie , Bass Nicholas , Bauer Michael , Beins Eva C. , Bergen Sarah E. , Birner Armin , Bøcker Pedersen Carsten , Bøen Erlend , Boks Marco P. , Bosch Rosa , Brum Murielle , Brumpton Ben M. , Brunkhorst-Kanaan Nathalie , Budde Monika , Bybjerg-Grauholm Jonas , Byerley William , Cairns Murray , Casas Miquel , Cervantes Pablo , Clarke Toni-Kim , Cruceanu Cristiana , Cuellar-Barboza Alfredo , Cunningham Julie , Curtis David , Czerski Piotr M. , Dale Anders M. , Dalkner Nina , David Friederike S. , Degenhardt Franziska , Djurovic Srdjan , Dobbyn Amanda L. , Douzenis Athanassios , Elvsåshagen Torbjørn , Escott-Price Valentina , Ferrier I. Nicol , Fiorentino Alessia , Foroud Tatiana M. , Forty Liz , Frank Josef , Frei Oleksandr , Freimer Nelson B. , Frisén Louise , Gade Katrin , Garnham Julie , Gelernter Joel , Giørtz Pedersen Marianne , Gizer Ian R. , Gordon Scott D. , Gordon-Smith Katherine , Greenwood Tiffany A. , Grove Jakob , Guzman-Parra José , Ha Kyooseob , Haraldsson Magnus , Hautzinger Martin , Heilbronner Urs , Hellgren Dennis , Herms Stefan , Hoffmann Per , Holmans Peter A. , Huckins Laura , Jamain Stéphane , Johnson Jessica S. , Kalman Janos L. , Kamatani Yoichiro , Kennedy James L. , Kittel-Schneider Sarah , Knowles James A. , Kogevinas Manolis , Koromina Maria , Kranz Thorsten M. , Kranzler Henry R. , Kubo Michiaki , Kupka Ralph , Kushner Steven A. , Lavebratt Catharina , Lawrence Jacob , Leber Markus , Lee Heon-Jeong , Lee Phil H. , Levy Shawn E. , Lewis Catrin , Liao Calwing , Lucae Susanne , Lundberg Martin , MacIntyre Donald J. , Magnusson Sigurdur H. , Maier Wolfgang , Maihofer Adam , Malaspina Dolores , Maratou Eirini , Martinsson Lina , Mattheisen Manuel , McCarroll Steven A. , McGregor Nathaniel W. , McGuffin Peter , McKay James D. , Medeiros Helena , Medland Sarah E. , Millischer Vincent , Montgomery Grant W. , Moran Jennifer L. , Morris Derek W. , Mühleisen Thomas W. , O’Brien Niamh , O’Donovan Claire , Loohuis Loes M. Olde , Oruc Lilijana , Papiol Sergi , Pardiñas Antonio F. , Perry Amy , Pfennig Andrea , Porichi Evgenia , Potash James B. , Quested Digby , Raj Towfique , Rapaport Mark H. , DePaulo J. Raymond , Regeer Eline J. , Rice John P. , Rivas Fabio , Rivera Margarita , Roth Julian , Roussos Panos , Ruderfer Douglas M. , Sánchez-Mora Cristina , Schulte Eva C. , Senner Fanny , Sharp Sally , Shilling Paul D. , Sigurdsson Engilbert , Sirignano Lea , Slaney Claire , Smeland Olav B. , Smith Daniel J. , Sobell Janet L. , Søholm Hansen Christine , Artigas Maria Soler , Spijker Anne T. , Stein Dan J. , Strauss John S. , Świątkowska Beata , Terao Chikashi , Thorgeirsson Thorgeir E. , Toma Claudio , Tooney Paul , Tsermpini Evangelia-Eirini , Vawter Marquis P. , Vedder Helmut , Walters James T. R. , Witt Stephanie H. , Xi Simon , Xu Wei , Yang Jessica Mei Kay , Young Allan H. , Young Hannah , Zandi Peter P. , Zhou Hang , Zillich Lea , Psychiatry HUNT All-In , Adolfsson Rolf , Agartz Ingrid , Alda Martin , Alfredsson Lars , Babadjanova Gulja , Backlund Lena , Baune Bernhard T. , Bellivier Frank , Bengesser Susanne , Berrettini Wade H. , Blackwood Douglas H. R. , Boehnke Michael , Børglum Anders D. , Breen Gerome , Carr Vaughan J. , Catts Stanley , Corvin Aiden , Craddock Nicholas , Dannlowski Udo , Dikeos Dimitris , Esko Tõnu , Etain Bruno , Ferentinos Panagiotis , Frye Mark , Fullerton Janice M. , Gawlik Micha , Gershon Elliot S. , Goes Fernando S. , Green Melissa J. , Grigoroiu-Serbanescu Maria , Hauser Joanna , Henskens Frans , Hillert Jan , Hong Kyung Sue , Hougaard David M. , Hultman Christina M. , Hveem Kristian , Iwata Nakao , Jablensky Assen V. , Jones Ian , Jones Lisa A. , S. Kahn René , Kelsoe John R. , Kirov George , Landén Mikael , Leboyer Marion , Lewis Cathryn M. , Li Qingqin S. , Lissowska Jolanta , Lochner Christine , Loughland Carmel , Martin Nicholas G. , Mathews Carol A. , Mayoral Fermin , McElroy Susan L. , McIntosh Andrew M. , McMahon Francis J. , Melle Ingrid , Michie Patricia , Milani Lili , Mitchell Philip B. , Morken Gunnar , Mors Ole , Mortensen Preben Bo , Mowry Bryan , Müller-Myhsok Bertram , Myers Richard M. , Neale Benjamin M. , Nievergelt Caroline M. , Nordentoft Merete , Nöthen Markus M. , O’Donovan Michael C. , Oedegaard Ketil J. , Olsson Tomas , Owen Michael J. , Paciga Sara A. , Pantelis Chris , Pato Carlos , Pato Michele T. , Patrinos George P. , Perlis Roy H. , Posthuma Danielle , Ramos-Quiroga Josep Antoni , Reif Andreas , Reininghaus Eva Z. , Ribasés Marta , Rietschel Marcella , Ripke Stephan , Rouleau Guy A. , Saito Takeo , Schall Ulrich , Schalling Martin , Schofield Peter R. , Schulze Thomas G. , Scott Laura J. , Scott Rodney J. , Serretti Alessandro , Weickert Cynthia Shannon , Smoller Jordan W. , Stefansson Hreinn , Stefansson Kari , Stordal Eystein , Streit Fabian , Sullivan Patrick F. , Turecki Gustavo , Vaaler Arne E. , Vieta Eduard , Vincent John B. , Waldman Irwin D. , Weickert Thomas W. , Werge Thomas , Wray Naomi R. , Zwart John-Anker , Biernacka Joanna M. , Nurnberger John I. , Cichon Sven , Edenberg Howard J. , Stahl Eli A. , McQuillin Andrew , Di Florio Arianna , Ophoff Roel A. , Andreassen Ole A. 
Published: September 2020

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD 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 eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.