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Genome-wide association study of over 40,000 bipolar disorder cases provides novel biological insights

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

Posted 18 Sep 2020
medRxiv DOI: 10.1101/2020.09.17.20187054

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, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic and calcium 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 and antiepileptics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, including druggable genes such as HTR6, MCHR1, DCLK3 and FURIN. This GWAS provides the best-powered BD polygenic scores to date, when applied in both European and diverse ancestry samples. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

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