Genomics yields biological and phenotypic insights into bipolar disorder
Authors: O’Connell Kevin S. , Koromina Maria , van der Veen Tracey , Boltz Toni , David Friederike S. , Kay Yang Jessica Mei , Lin Keng-Han , Wang Xin , Coleman Jonathan R. I. , Mitchell Brittany L. , McGrouther Caroline C. , Rangan Aaditya V. , Lind Penelope A. , Koch Elise , Harder Arvid , Parker Nadine , Bendl Jaroslav , Adorjan Kristina , Agerbo Esben , Albani Diego , Alemany Silvia , Alliey-Rodriguez Ney , Als Thomas D. , Andlauer Till F. M. , Antoniou Anastasia , Ask Helga , Bass Nicholas , Bauer Michael , Beins Eva C. , Bigdeli Tim B. , Bøcker Pedersen Carsten , Boks Marco P. , Børte Sigrid , Bosch Rosa , Brum Murielle , Brumpton Ben M. , Brunkhorst-Kanaan Nathalie , Budde Monika , Bybjerg-Grauholm Jonas , Byerley William , Cabana-Domínguez Judit , Cairns Murray J. , Carpiniello Bernardo , Casas Miquel , Cervantes Pablo , Chatzinakos Chris , Chen Hsi-Chung , Clarence Tereza , Clarke Toni-Kim , Claus Isabelle , Coombes Brandon , Corfield Elizabeth C. , Cruceanu Cristiana , Cuellar-Barboza Alfredo , Czerski Piotr M. , Dafnas Konstantinos , Dale Anders M. , Dalkner Nina , Degenhardt Franziska , DePaulo J. Raymond , Djurovic Srdjan , Drange Ole Kristian , Escott-Price Valentina , Fanous Ayman H. , Fellendorf Frederike T. , Ferrier I. Nicol , Forty Liz , Frank Josef , Frei Oleksandr , Freimer Nelson B. , Fullard John F. , Garnham Julie , Gizer Ian R. , Gordon Scott D. , Gordon-Smith Katherine , Greenwood Tiffany A. , Grove Jakob , Guzman-Parra José , Ha Tae Hyon , Hahn Tim , Haraldsson Magnus , Hautzinger Martin , Havdahl Alexandra , Heilbronner Urs , Hellgren Dennis , Herms Stefan , Hickie Ian B. , Hoffmann Per , Holmans Peter A. , Huang Ming-Chyi , Ikeda Masashi , Jamain Stéphane , Johnson Jessica S. , Jonsson Lina , Kalman Janos L. , Kamatani Yoichiro , Kennedy James L. , Kim Euitae , Kim Jaeyoung , Kittel-Schneider Sarah , Knowles James A. , Kogevinas Manolis , Kranz Thorsten M. , Krebs Kristi , Kushner Steven A. , Lavebratt Catharina , Lawrence Jacob , Leber Markus , Lee Heon-Jeong , Liao Calwing , Lucae Susanne , Lundberg Martin , MacIntyre Donald J. , Maier Wolfgang , Maihofer Adam X. , Malaspina Dolores , Manchia Mirko , Maratou Eirini , Martinsson Lina , Mattheisen Manuel , McGregor Nathaniel W. , McInnis Melvin G. , McKay James D. , Medeiros Helena , Meyer-Lindenberg Andreas , Millischer Vincent , Morris Derek W. , Moutsatsou Paraskevi , Mühleisen Thomas W. , O’Donovan Claire , Olsen Catherine M. , Panagiotaropoulou Georgia , Papiol Sergi , Pardiñas Antonio F. , Park Hye Youn , Perry Amy , Pfennig Andrea , Pisanu Claudia , Potash James B. , Quested Digby , Rapaport Mark H. , Regeer Eline J. , Rice John P. , Rivera Margarita , Schulte Eva C. , Senner Fanny , Shadrin Alexey , Shilling Paul D. , Sigurdsson Engilbert , Sindermann Lisa , Sirignano Lea , Siskind Dan , Slaney Claire , Sloofman Laura G. , Smeland Olav B. , Smith Daniel J. , Sobell Janet L. , Soler Artigas Maria , Stein Dan J. , Stein Frederike , Su Mei-Hsin , Sung Heejong , Świątkowska Beata , Terao Chikashi , Tesfaye Markos , Tesli Martin , Thorgeirsson Thorgeir E. , Thorp Jackson G. , Toma Claudio , Tondo Leonardo , Tooney Paul A. , Tsai Shih-Jen , Tsermpini Evangelia Eirini , Vawter Marquis P. , Vedder Helmut , Vreeker Annabel , Walters James T. R. , Winsvold Bendik S. , Witt Stephanie H. , Won Hong-Hee , Ye Robert , Young Allan H. , Zandi Peter P. , Zillich Lea ,   23andMe Research Team,   Estonian Biobank research team,   Genoplan Research Team,   HUNT All-In Psychiatry,   PGC-FG Single cell working group,   Genomic Psychiatry Cohort (GPC) Investigators, Adolfsson Rolf , Alda Martin , Alfredsson Lars , Backlund Lena , Baune Bernhard T. , Bellivier Frank , Bengesser Susanne , Berrettini Wade H. , Biernacka Joanna M. , Boehnke Michael , Børglum Anders D. , Breen Gerome , Carr Vaughan J. , Catts Stanley , Cichon Sven , Corvin Aiden , Craddock Nicholas , Dannlowski Udo , Dikeos Dimitris , 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 A. , Hjerling-Leffler Jens , Hougaard David M. , Hveem Kristian , Iwata Nakao , Jones Ian , Jones Lisa A. , Kahn René S. , Kelsoe John R. , Kircher Tilo , Kirov George , Kuo Po-Hsiu , Landén Mikael , Leboyer Marion , Li Qingqin S. , Lissowska Jolanta , Lochner Christine , Loughland Carmel , Luykx Jurjen J. , Martin Nicholas G. , Mathews Carol A. , Mayoral Fermin , McElroy Susan L. , McIntosh Andrew M. , McMahon Francis J. , Medland Sarah E. , Melle Ingrid , Milani Lili , Mitchell Philip B. , Morken Gunnar , Mors Ole , Mortensen Preben Bo , Müller-Myhsok Bertram , Myers Richard M. , Myung Woojae , Neale Benjamin M. , Nievergelt Caroline M. , Nordentoft Merete , Nöthen Markus M. , Nurnberger John I. , O’Donovan Michael C. , Oedegaard Ketil J. , Olsson Tomas , Owen Michael J. , Paciga Sara A. , Pantelis Christos , Pato Carlos N. , Pato Michele T. , Patrinos George P. , Pawlak Joanna M. , Ramos-Quiroga Josep Antoni , Reif Andreas , Reininghaus Eva Z. , Ribasés Marta , Rietschel Marcella , Ripke Stephan , Rouleau Guy A. , Roussos Panos , Saito Takeo , Schall Ulrich , Schalling Martin , Schofield Peter R. , Schulze Thomas G. , Scott Laura J. , Scott Rodney J. , Serretti Alessandro , Smoller Jordan W. , Squassina Alessio , Stahl Eli A. , 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 Cynthia S. , Weickert Thomas W. , Werge Thomas , Whiteman David C. , Zwart John-Anker , Edenberg Howard J. , McQuillin Andrew , Forstner Andreas J. , Mullins Niamh , Di Florio Arianna , Ophoff Roel A. , Andreassen Ole A. ,   the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Published: October 2023

AbstractBipolar disorder (BD) is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n=158,036 BD cases, 2.8 million controls), combining Clinical, Community, and Self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a 4-fold increase over previous findings3, and identified a novel ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of BD. Genes prioritised through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in BD cases4, highlighting convergence of common and rare variant signals. We report differences in genetic architecture of BD depending on the source of patient ascertainment and on BD-subtype (BDI and BDII). Several analyses implicate specific cell types in BD pathophysiology, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide novel insights into the genetic architecture and biological underpinnings of BD.