Genomics yields biological and phenotypic insights into bipolar disorder

作者：K. S. O’Connell, M. Koromina, Tracey van der Veen, T. Boltz, F. David, J. M. K. Yang, Keng-Han Lin, Xin Wang, Jonathan R. I. Coleman, B. L. Mitchell, C. McGrouther, A. Rangan, P. Lind, E. Koch, A. Harder, N. Parker, J. Bendl, K. Adorjan, E. Agerbo, D. Albani, S. Alemany, N. Alliey-Rodriguez, T. Als, Till F M Andlauer, A. Antoniou, H. Ask, Nicholas J. Bass, Michael Bauer, E. Beins, T. Bigdeli, C. B. Pedersen, M. Boks, S. Børte, R. Bosch, M. Brum, B. M. Brumpton, N. Brunkhorst-Kanaan, M. Budde, J. Bybjerg-Grauholm, W. Byerley, J. Cabana-Domínguez, Murray J. Cairns, B. Carpiniello, M. Casas, P. Cervantes, C. Chatzinakos, Hsi- Chen, Tereza Clarence, Toni‐Kim Clarke, I. Claus, Brandon J. Coombes, Elizabeth C. Corfield, C. Cruceanu, A. Cuellar-Barboza, P. Czerski, K. Dafnas, A. Dale, N. Dalkner, Franziska Degenhardt, J. DePaulo, S. Djurovic, O. Drange, V. Escott-Price, A. Fanous, F. Fellendorf, I. N. Ferrier, L. Forty, J. Frank, O. Frei, Nelson B. Freimer, J. Fullard, J. Garnham, I. Gizer, S. Gordon, K. Gordon-Smith, Tiffany A. Greenwood, Jakob Grove, J. Guzmán-Parra, Tae Hyon Ha, Tim Hahn, M. Haraldsson, M. Hautzinger, A. Havdahl, U. Heilbronner, Dennis Hellgren, S. Herms, I. Hickie, P. Hoffmann, P. Holmans, Ming-Chyi Huang, M. Ikeda, S. Jamain, Jessica S. Johnson, L. Jonsson, J. Kalman, Y. Kamatani, James L Kennedy, Euitae Kim, Jaeyoung Kim, S. Kittel-Schneider, James A Knowles, M. Kogevinas, T. Kranz, Kristi Krebs, Steven A. Kushner, C. Lavebratt, J. Lawrence, M. Leber, Heon-Jeong Lee, Calwing Liao, S. Lucae, M. Lundberg, D. Macintyre, W. Maier, A. Maihofer, D. Malaspina, M. Manchia, E. Maratou, L. Martinsson, M. Mattheisen, N. McGregor, Melvin G. McInnis, James D. Mckay, H. Medeiros, Andreas Meyer-Lindenberg, V. Millischer, Derek W. Morris, P. Moutsatsou, Thomas W. Mühleisen, C. O’Donovan, C. Olsen, G. Panagiotaropoulou, S. Papiol, A. Pardiñas, H. Park, A. Perry, Andrea Pfennig, C. Pisanu, J. Potash, Digby Quested, Mark H. Rapaport, E. J. Regeer, John P. Rice, M. Rivera, Eva C. Schulte, F. Senner, A. Shadrin, P. Shilling, E. Sigurdsson, L. Sindermann, L. Sirignano, D. Siskind, C. Slaney, Laura G. Sloofman, O. Smeland, Daniel J Smith, J. Sobell, M. Soler Artigas, D. J. Stein, F. Stein, Mei-Hsin Su, Heejong Sung, B. Świątkowska, C. Terao, M. Tesfaye, M. Tesli, T. Thorgeirsson, Jackson G. Thorp, Claudio Toma, L. Tondo, P. Tooney, Shih-Jen Tsai, E. Tsermpini, M. Vawter, H. Vedder, A. Vreeker, James T. R. Walters, B. Winsvold, S. Witt, Hong-Hee Won, Robert Ye, A. H. Young, P. Zandi, Lea Zillich, Byung Lee, Ji-Woong Kim, Young Kee Lee, Joon Ho Kang, M. Cheon, Dong Jun Kim, Mihaela Aslan, Philip D Harvey, Grant D. Huang, R. Adolfsson, M. Alda, Lars Alfredsson, L. Backlund, B. Baune, F. Bellivier, S. Bengesser, W. Berrettini, Joanna M. Biernacka, M. Boehnke, A. Børglum, G. Breen, V. Carr, S. Catts, S. Cichon, A. Corvin, N. Craddock, U. Dannlowski, D. Dikeos, B. Étain, P. Ferentinos, Mark A. Frye, J. Fullerton, M. Gawlik, E. Gershon, F. Goes, M. Green, M. Grigoroiu-Serbanescu, Joanna Hauser, F. Henskens, J. Hjerling-Leffler, D. Hougaard, K. Hveem, Nakao Iwata, Ian Jones, Lisa A Jones, René S Kahn, J. Kelsoe, T. Kircher, G. Kirov, Po-Hsiu Kuo, M. Landén, M. Leboyer, Qingqin S. Li, J. Lissowska, C. Lochner, C. Loughland, J. Luykx, Nicholas G. Martin, C. A. Mathews, F. Mayoral, Susan L. McElroy, Andrew M. McIntosh, F. McMahon, S. Medland, I. Melle, L. Milani, P. Mitchell, G. Morken, Ole Mors, P. Mortensen, B. Müller-Myhsok, R. Myers, W. Myung, B. Neale, C. Nievergelt, M. Nordentoft, M. Nöthen, J. Nurnberger, M. O’Donovan, K. Oedegaard, Tomas Olsson, M. Owen, S. Paciga, Christos Pantelis, Carlos N. Pato, M. Pato, G. Patrinos, Joanna M Pawlak, J. Ramos-Quiroga, A. Reif, E. Reininghaus, M. Ribasés, Marcella Rietschel, S. Ripke, G. Rouleau, P. Roussos, Takeo Saito, U. Schall, M. Schalling, P. R. Schofield, T. G. Schulze, Laura Scott, Rodney J. Scott, A. Serretti, J. Smoller, A. Squassina, E. Stahl, H. Stefánsson, Kári Stefánsson, E. Stordal, F. Streit, P. Sullivan, G. Turecki, A. Vaaler, Eduard Vieta, John B. Vincent, Irwin D. Waldman, C. Weickert, T. Weickert, T. Werge, D. Whiteman, J. Zwart, H. Edenberg, A. McQuillin, A. Forstner, N. Mullins, A. Di Florio, R. Ophoff, O. Andreassen · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-024-08468-9 · 被引用次数：178 · 研究领域：Medicine

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. Using multi-ancestry genome-wide association study and fine-mapping, 298 loc...