Mapping the genetic landscape across 14 psychiatric disorders

作者：Andrew D. Grotzinger, Josefin Werme, Wouter J. Peyrot, Oleksandr Frei, Christiaan de Leeuw, Lucy Bicks, Qiuyu Guo, Michael Margolis, Brandon J. Coombes, Anthony Batzler, Vanessa Pazdernik, Joanna M. Biernacka, Ole A. Andreassen, Verneri Anttila, Anders D. Børglum, Gerome Breen, Na Cai, Ditte Demontis, Howard J. Edenberg, Stephen V. Faraone, Barbara Franke, Michael J. Gandal, Joel Gelernter, Alexander S. Hatoum, John M. Hettema, Emma C. Johnson, Katherine Jonas, James A. Knowles, Karestan C. Koenen, Adam X. Maihofer, Travis T. Mallard, Manuel Mattheisen, Karen S. Mitchell, Benjamin M. Neale, Caroline M. Nievergelt, John I. Nürnberger, Kevin S. O’Connell, Roseann E. Peterson, Elise Robinson, Sandra Sanchez‐Roige, Susan L. Santangelo, Jeremiah M. Scharf, Hreinn Stefansson, Kari Stefansson, Murray B. Stein, Nora I. Strom, Laura M. Thornton, Elliot M. Tucker–Drob, Brad Verhulst, Irwin D. Waldman, G. Bragi Walters, Naomi R. Wray, Dongmei Yu, Daniel E. Adkins, Georg W. Alpers, Helga Ask, Síntia Belangero, Ottar Bjerkeset, Sigrid Børte, Sandra A. Brown, Enrique Castelao, Hilary Coon, William E. Copeland, Elizabeth C. Corfield, Darina Czamara, Jürgen Deckert, Anna R. Docherty, Katharina Domschke, Ole Kristian Drange, Thalia C. Eley, Angelika Erhardt, Andreas J. Forstner, Miguel Garcia‐Argibay, Scott D. Gordon, Ian B. Hickie, Iiris Hovatta, Matthew H. Iveson, James L. Kennedy, Henrik Larsson, Daniel Levey, Christine Löchner, Michelle K. Lupton, Hermine HM Maes, Eduard Maron, Nicholas G. Martin, Sandra Meier, Christiane A. Melzig, Brittany L. Mitchell, Teemu Palviainen, Giorgio Pistis, Martin Preisig, Börge Schmidt, Johannes Schumacher, Andrey A. Shabalin, Anne Heidi Skogholt, Dan J. Stein, Eystein Stordal, Andreas Ströhle, Elisa Tasanko, Laurent F. Thomas, Henning Tiemeier, Heike Weber, Bendik S. Winsvold, Clement C. Zai, Gwyneth Zai, John‐Anker Zwart, Silvia Alemany, Claiton H.D. Bau, Dorret I. Boomsma, Rosa Bosch, Isabell Brikell, Christie L. Burton, Miguel Casas, Bru Cormand, Jennifer Crosbie, Alysa E. Doyle, Josephine Elia, Joseph Glessner, Eugênio H. Grevet, Jan Haavik, Alexandra Havdahl, Ziarih Hawi, Anke Hinney, Daniel P. Howrigan, Marieke Klein, Henry R. Kranzler, Jonna Kuntsi, K. Langley, Klaus‐Peter Lesch, Calwing Liao, Sandra K. Loo, James J. McGough, Sarah E. Medland, Nina Roth Mota, Michael O‘Donovan, Daniëlle Posthuma, Josep Antoni Ramos‐Quiroga, Andreas Reif, Marta Ribasés, Diego Luiz Rovaris, Russell Schachar, Stephen W. Scherer, Yingjie Shi, María Soler Artigas, Edmund Sonuga‐Barke, Hans‐Christoph Steinhausen, Ludger Tebartz van Elst, Martin Tesli, Raymond K. Walters, Stephanie H. Witt, Yanli Zhang‐James, Edwin H. Cook, Jakob Grove, Susan S. Kuo, Joseph Piven, Stephan Sanders, Mohammed Jashim Uddin, Jacob Vorstman, Varun Warrier, Lauren A. Weiss, Martin Alda, Lars Alfredsson, Till F. M. Andlauer, Nicholas Bass, Anthony Batzler, Bernhard T. Baune, Eva C. Beins, Tim B. Bigdeli, Sven Cichon, Jonathan R. I. Coleman, Alfredo B. Cuéllar‐Barboza, Udo Dannlowski, Friederike S. David, Josef Frank, Janice M. Fullerton, Fernando S. Goes, Maria Grigoroiu‐Serbânescu, Per Hoffmann, János Kálmán, Kristi Krebs, Mikael Landén, Cathryn M. Lewis, Qingqin S. Li, Penelope A. Lind, Jurjen J. Luykx, Mirko Manchia, Morten Mattingsdal, Andrew M. McIntosh, Andrew McQuillin, Anna Meloni, Lili Milani, Philip B. Mitchell, Derek W. Morris, Niamh Mullins, Woojae Myung, John I. Nürnberger, Roel A. Ophoff, Michael J. Owen, George P. Patrinos, Claudia Pisanu, James J. Prisciandaro, Eva Z. Reininghaus, John P. Rice, Marcella Rietschel, Eva C. Schulte, Alessandro Serretti, Lea Sirignano, Alessio Squassina, Fabian Streit, Jana Strohmaier, Tracey van der Veen, Marquis P. Vawter, John B. Vincent, Peter P. Zandi, Lea Zillich, Roger A.H. Adan, Andreas Birgegård, Cynthia M. Bulik, Christian Dina, Monika Dmitrzak‐Węglarz, Elisa Docampo, Karin Egberts, Fernando Fernández‐Aranda, Katrin Elisabeth Giel, Philip Gorwood, Christopher Hübel, James I. Hudson, Susana Jiménez‐Múrcia, Jennifer Jordan, Gursharan Kalsi, Jaakko Kaprio, Leila Karhunen, Martien J. Kas, Martin A. Kennedy, Janne Tidselbak Larsen, Lisa Lilenfeld, Alessio Maria Monteleone, Melissa A. Munn‐Chernoff, Benedetta Nacmias, Liselotte Petersen, Dalila Pinto, Anu Raevuori, Nicolas Ramoz, Valdo Ricca, Marion Roberts, Filip Rybakowski, Ulrike Schmidt, Alexandra Schosser, Sandro Sorbi, Michael Strober, Hunna J. Watson, Stephan Zipfel, Mark J. Adams, Michael E. Benros, Rodrigo A. Bressan, Enda M. Byrne, Carolina Muniz Carvalho, Boris Chaumette, Lucía Colodro‐Conde, Eske M. Derks, Erin C. Dunn, Chiara Fabbri, Giuseppe Fanelli, Jerome C. Foo, Ary Gadelha, Zachary F. Gerring, Hans J. Grabe, Andrew C. Heath, Kelli Lehto, Douglas F. Levinson, Glyn Lewis, Vanessa Ota, Pedro Mário Pan, Peristera Paschou, James B. Potash, Brien P. Riley, Giovanni Abrahão Salum, Marcos Santoro, Jackson G. Thorp, Sandra Van der Auwera, Bradley T. Webb, Timothy B. Baker, Danielle M. Dick, Dmitriy Drichel, Lindsay A. Farrer, Nathan Gaddis, Dana B. Hancock, John E. Hokanson, Jouke‐Jan Hottenga, Eric O. Johnson, Pamela A. F. Madden, Mary L. Marazita, Jesse A. Marks, Daniel W. McNeil, Michael Nothnagel, Bryan C. Quach, Nancy L. Saccone, Nancy Y. A. Sey, Richard Sherva, Scott Vrieze, Alex Waldrop, Georg Winterer, Kendra A. Young, Stephanie Zellers, Cathy L. Barr, Csaba Barta, Katharina Bey, O. Joseph Bienvenu, Julia Boberg, Jonas Bybjerg‐Grauholm, Adrian Camarena, Beatríz Camarena, Daniëlle C. Cath, James J. Crowley, Andrea Dietrich, Peter Falkai, Thomas Fernandez, Daniel Geller, Marco A. Grados, Erica Greenberg, Edna Grünblatt, Kristen Hagen, Gregory L. Hanna, Bjarne Hansen, Gary A. Heiman, Pieter J. Hoekstra, David M. Hougaard, Norbert Kathmann, Julia Klawohn, Gerd Kvale, Nuria Lanzagorta, Stéphanie Le Hellard, Fabìo Macciardi, Brion S. Maher, Irene A. Malaty, David Mataix–Cols, Carol A. Mathews, Nicole McLaughlin, Eurı́pedes Constantino Miguel, Kirsten Müller‐Vahl, Humberto Nicolini, Erika L. Nurmi, Michael S. Okun, Raquel Rabionet, Alfredo Ramı́rez, Renata Rizzo, Cristina Rodriguez‐Fontenla, Paul Sandor, Elles de Schipper, Harvey S. Singer, Eric A. Storch, Jeremy Veenstra‐VanderWeele, Michael Wagner, Christopher Walker, Søren Bo Andersen, Laura J. Bierut, Chia‐Yen Chen, Nikolaos P. Daskalakis, Seth G. Disner, Anna R. Docherty, Norah C. Feeny, Lana Ruvolo Grasser, Magali Haas, Kelly Harrington, Victor Hesselbrock, Mohammed Ibrahim, Şeyma Katrinli, Nathan A. Kimbrel, Jessica L. Maples‐Keller, Jacquelyn L. Meyers, Janitza L. Montalvo‐Ortiz, C. Phillip Morris, Robert H. Pietrzak, Renato Polimanti, Richard J. Rosenblum, Barbara O. Rothbaum, Bart P. F. Rutten, Soraya Seedat, Alicia K. Smith, Ralph E. Tarter, Muhammad Ayub, Dominique Campion, David Cohen, Angèle Consoli, Marta Di Forti, Johan G. Eriksson, Olga Fedorenko, Robert Freedman, Raul R. Gainetdinov, Marianna Giannitelli, Ina Giegling, Stephen J. Glatt, Stephanie Godard, Olivier Guillin, Annette M. Hartmann, Svetlana Ivanova, А.О. Кибитов, Bettina Konte, Claudine Laurent‐Levinson, Аnastasia Levchenko, Robin Murray, Merete Nordentoft, Cristiano Noto, Diego Quattrone, Dan Rujescu, Safaa Saker-Delye, Sibylle G. Schwab, Florence Thibaut, James Walters, Thomas Werge, Dieter B. Wildenauer, Arpana Agrawal, David A. A. Baranger, Jason D. Boardman, Joseph M. Boden, Ryan Bogdan, Karhleen K. Bucholz, Doo‐Sup Choi, Sarah M. C. Colbert, Joseph D. Deak, Nancy Diazgranados, Alexis C. Edwards, Alison Goate, David Goldman, Laura M. Hack, Kathleen Mullan Harris, Sarah M. Hartz, Caroline Hayward, John K. Hewitt, Christian J. Hopfer, Victor M. Karpyak, Kenneth Krauter, Evgeny Krupitsky, Samuel Kuperman, Jari Lahti, Marius Lahti‐Pulkkinen, Dongbing Lai, Alex P. Miller, Abraham A. Palmer, Rohn H. Palmer, John F. Pearson, Bernice Porjesz, Ulrich W. Preuss, Daniel Rosenblum, Norbert Scherbaum, Michael M. Vanyukov, Tamara L. Wall, Robbee Wedow, Stanley H. Weiss, Leah Wetherill, Norbert Wodarz, Haitao Zhang, Hongyu Zhao, Hang Zhou, Peter Zill, Phil H. Lee, Kenneth S. Kendler, Jordan W. Smoller · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09820-3 · 被引用次数：85 · 研究领域：Genetic Associations and Epidemiology、Schizophrenia research and treatment、Neurotransmitter Receptor Influence on Behavior

Psychiatric disorders display high levels of comorbidity and genetic overlap1,2, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder3, genomic methods have revealed that the majority of genetic signal is shared4. While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses5, the full scope of shared and disorder-specific genetic influences remains poorly defined. Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases). Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci. The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap6 and local genetic correlation and very few disorder-specific loci. The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors. The shared genetic signal across the SB factor was substan...