Genomics yields biological and phenotypic insights into bipolar disorder

O'Connell, Kevin S., Koromina, Maria, van der Veen, Tracey, Boltz, Toni, David, Friederike S., Yang, Jessica Mei Kay, 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., Pedersen, Carsten Bøcker, 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 ORCID: https://orcid.org/0000-0003-1784-5483, Fanous, Ayman H., Fellendorf, Frederike T., Ferrier, I. Nicol, Forty, Elizabeth, 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. ORCID: https://orcid.org/0000-0003-0870-9412, 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, Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, 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, Swiatkowska, 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, Lee, Byung-Chul, Kim, Ji-Woong, Lee, Young Kee, Kang, Joon Ho, Cheon, Myeong Jae, Kim, Dong Jun, Aslan, Mihaela, Harvey, Philip D., Huang, Grant D., 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. ORCID: https://orcid.org/0000-0001-7073-2379, 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 ORCID: https://orcid.org/0000-0003-0338-2748, Ophoff, Roel A., Andreassen, Ole A., van der Veen, Tracey and Siskind, Dan 2025. Genomics yields biological and phenotypic insights into bipolar disorder. Nature 10.1038/s41586-024-08468-9 Item availability restricted.

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Abstract

Bipolar disorder 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 cases with bipolar disorder, 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 fourfold increase over previous findings3, and identified an 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 bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine
Publisher:	Nature Research
ISSN:	0028-0836
Date of First Compliant Deposit:	31 January 2025
Date of Acceptance:	28 November 2024
Last Modified:	03 Feb 2025 12:15
URI:	https://orca.cardiff.ac.uk/id/eprint/175796

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