Genomics yields biological and phenotypic insights into bipolar disorder

作者：Kevin S. O’Connell, Maria Koromina, Tracey van der Veen, Toni Boltz, Friederike S. David, Jessica Yang, Keng‐Han Lin, Xin Wang, Jonathan R. I. Coleman, Brittany L. Mitchell, Caroline C. McGrouther, Aaditya V. Rangan, Penelope A. Lind, Elise Koch, Arvid Harder, Nadine Parker, Jaroslav Bendl, Kristina Adorjan, Esben Agerbo, Diego Albani, Silvia Alemany, Ney Alliey‐Rodriguez, Thomas D. Als, Till F. M. Andlauer, Anastasia Antoniou, Helga Ask, Nicholas Bass, Michael Bauer, Eva C. Beins, Tim B. Bigdeli, Carsten Bøcker Pedersen, Marco P. Boks, Sigrid Børte, Rosa Bosch, Murielle Brum, Ben Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg‐Grauholm, William Byerley, Judit Cabana‐Domínguez, Murray J. Cairns, Bernardo Carpiniello, Miguel Casas, Pablo Cervantes, Chris Chatzinakos, Hsi‐Chung Chen, Tereza Clarence, Toni‐Kim Clarke, Isabelle Claus, Brandon J. Coombes, Elizabeth C. Corfield, Cristiana Cruceanu, Alfredo B. Cuéllar‐Barboza, Piotr M. Czerski, Konstantinos Dafnas, Anders M. Dale, Nina Dalkner, Franziska Degenhardt, J. Raymond DePaulo, Srdjan Djurovic, Ole Kristian Drange, Valentina Escott‐Price, Ayman H. Fanous, Frederike T. Fellendorf, I. Nicol Ferrier, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B. Freimer, John F. Fullard, Julie Garnham, Ian R. Gizer, Scott D. Gordon, Katherine Gordon‐Smith, Tiffany A. Greenwood, Jakob Grove, José Guzmán‐Parra, Tae Hyon Ha, Tim Hahn, Magnús Haraldsson, Martin Hautzinger, Alexandra Havdahl, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Ian B. Hickie, Per Hoffmann, Peter Holmans, Ming‐Chyi Huang, Masashi Ikeda, Stéphane Jamain, Jessica Johnson, Lina Jönsson, János Kálmán, Yoichiro Kamatani, James L. Kennedy, Euitae Kim, Jaeyoung Kim, Sarah Kittel‐Schneider, James A. Knowles, Manolis Kogevinas, Thorsten M. Kranz, Kristi Krebs, Steven A. Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon‐Jeong Lee, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J. MacIntyre, Wolfgang Maier, Adam X. Maihofer, Dolores Malaspina, Mirko Manchia, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Nathaniel W. McGregor, Melvin G. McInnis, James McKay, Helena Medeiros, Andreas Meyer‐Lindenberg, Vincent Millischer, Derek W. Morris, Paraskevi Moutsatsou, Thomas W. Mühleisen, Claire O’Donovan, Catherine M. Olsen, Georgia Panagiotaropoulou, Sergi Papiol, Antonio F. Pardiñas, Hye Youn Park, Amy Perry, Andrea Pfennig, Claudia Pisanu, James B. Potash, Digby Quested, Mark Hyman Rapaport, Eline J. Regeer, John P. Rice, Margarita Rivera, Eva C. Schulte, Fanny Senner, Alexey Shadrin, Paul D. Shilling, Engilbert Sigurðsson, Lisa Sindermann, Lea Sirignano, Dan Siskind, Claire Slaney, Laura Sloofman, Olav B. Smeland, Daniel J. Smith, Janet L. Sobell, María Soler Artigas, Dan J. Stein, Frederike Stein, Mei‐Hsin Su, Heejong Sung, Beata Świątkowska, Chikashi Terao, Markos Tesfaye, Martin Tesli, Thorgeir E. Thorgeirsson, Jackson G. Thorp, Claudio Toma, Leonardo Tondo, Paul A. Tooney, Shih‐Jen Tsai, Evangelia Eirini Tsermpini, Marquis P. Vawter, Helmut Vedder, Annabel Vreeker, James Walters, Bendik S. Winsvold, Stephanie H. Witt, Hong‐Hee Won, Robert Ye, Allan H. Young, Peter P. Zandi, Lea Zillich, HUNT All-In Psychiatry, PGC-FG Single cell working group, Genomic Psychiatry Cohort (GPC) Investigators, Rolf Adolfsson, Martin Alda, Lars Alfredsson, Lena Backlund, Bernhard T. Baune, Frank Bellivier, Susanne Bengesser, Wade H. Berrettini, Joanna M. Biernacka, Michael Boehnke, Anders D. Børglum, Gerome Breen, Vaughan J. Carr, Stanley V. Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Bruno Étain, Panagiotis Ferentinos, Mark A. Frye, Janice M. Fullerton, Micha Gawlik, Elliot S. Gershon, Fernando S. Goes, Melissa J. Green, Maria Grigoroiu‐Serbânescu, Joanna Hauser, Frans Henskens, Jens Hjerling‐Leffler, David M. Hougaard, Kristian Hveem, Nakao Iwata, Ian Jones, Lisa Jones, René S. Kahn, John R. Kelsoe, Tilo Kircher, George Kirov, Po‐Hsiu Kuo, Mikael Landén, Marion Leboyer, Qingqin S. Li, Jolanta Lissowska, Christine Löchner, Carmel Loughland, Jurjen J. Luykx, Nicholas G. Martin, Carol A. Mathews, Fermín Mayoral, Susan L. McElroy, Andrew M. McIntosh, Francis J. McMahon, Sarah E. Medland, Ingrid Melle, Lili Milani, Philip B. Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller‐Myhsok, R Myers, Woojae Myung, Benjamin M. Neale, Caroline M. Nievergelt, Merete Nordentoft, Markus M. Nöthen, John I. Nürnberger, Michael O‘Donovan, Ketil J. Øedegaard, Tomas Olsson, Michael J. Owen, Sara A. Paciga, Christos Pantelis, Carlos N. Pato, Michele T. Pato, George P. Patrinos, Joanna Pawlak, Josep Antoni Ramos‐Quiroga, Andreas Reif, Eva Z. Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A. Rouleau, Panos Roussos, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R. Schofield, Thomas G. Schulze, Laura J. Scott, Rodney J. Scott, Alessandro Serretti, Jordan W. Smoller, Alessio Squassina, Eli A. Stahl, Hreinn Stefánsson, Kāri Stefánsson, Eystein Stordal, Fabian Streit, Patrick F. Sullivan, Gustavo Turecki, Arne E. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, Cynthia Shannon Weickert, Thomas W. Weickert, Thomas Werge, David C. Whiteman, John‐Anker Zwart, Howard J. Edenberg, Andrew McQuillin, Andreas J. Forstner, Niamh Mullins, Arianna Di Florio, Roel A. Ophoff, Ole A. Andreassen · 发表于：medRxiv · 年份：2023 · DOI：10.1101/2023.10.07.23296687 · 被引用次数：22 · 研究领域：Genetic Associations and Epidemiology、Genetic Syndromes and Imprinting、Genomic variations and chromosomal abnormalities

Abstract Bipolar disorder (BD) is a leading contributor to the global burden of disease 1 . Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown 2 . 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 findings 3 , 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 cases 4 , 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.