Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects

作者：Worrawat Engchuan, Omar Shanta, Kuldeep Kumar, Jeffrey R. MacDonald, Bhooma Thiruvahindrapuram, Omar Hamdan, Marieke Klein, Adam X. Maihofer, James P. Guevara, Oanh Hong, Guillaume Huguet, M Sacks, Mohammad Ahangari, Rayssa M.M.W. Feitosa, Kara Han, Marla Mendes de Aquino, Xiaopu Zhou, Nelson X. Bautista, Giovanna Pellecchia, Zhouzhi Wang, Daniele Merico, Ryan K. C. Yuen, Brett Trost, Ida E. Sønderby, Mark J. Adams, Rolf Adolfsson, Ingrid Agartz, Allison E. Aiello, Martin Alda, Judith Allardyce, Ananda B. Amstadter, Till F. M. Andlauer, Ole A. Andreassen, María S. Artigas, S. Bryn Austin, Muhammad Ayub, Dewleen G. Baker, Nick Bass, Bernhard T. Baune, Maximilian Bayas, Klaus Berger, Joanna M. Biernacka, Tim B. Bigdeli, Jonathan I. Bisson, Douglas Blackwood, Marco P. Boks, David Braff, Elvira Bramon, Gerome Breen, T. Brueckl, Richard A. Bryant, Cynthia M. Bulik, Joseph D. Buxbaum, Murray J. Cairns, José Miguel Caldas‐de‐Almeida, Megan Campbell, Dominique Campion, Vaughan J. Carr, Enrique Castelao, Boris Chaumette, Sven Cichon, David Cohen, Aiden Corvin, Nick Craddock, Jennifer Crosbie, Darina Czamara, Udo Dannlowski, Franziska Degenhardt, Douglas L. Delahanty, Astrid Dempfle, Guillaume Desachy, Arianna Di Florio, Faith Dickerson, Srdjan Djurovic, Katharina Domschke, Lisa Douglas, Ole Kristian Drange, Laramie E. Duncan, Howard J. Edenberg, Tõnu Esko, Steve Faraone, Norah C. Feeny, Andreas J. Forstner, Barbara Franke, Mark A. Frye, Dong‐Jing Fu, Janice M. Fullerton, А. Э. Гареева, Linda Garvert, Justine M. Gatt, Pablo V. Gejman, Daniel H. Geschwind, Ina Giegling, Stephen J. Glatt, Joe Glessner, Fernando S. Goes, Katherine Gordon‐Smith, Hans J. Grabe, Melissa J. Green, Michael F. Green, Tiffany A. Greenwood, Maria Grigoroiu‐Serbânescu, Raquel E. Gur, Ruben C. Gur, José Guzmán‐Parra, Jan Haavik, Markus Hahn, Håkon Håkonarson, Joachim Hallmayer, Marian L. Hamshere, Annette M. Hartmann, Arsalan Hassan, Caroline Hayward, Johannes Hebebrand, Sian Hemmings, Stefan Herms, Marisol Herrera-Rivero, Anke Hinney, Georg Homuth, Andrés Ingason, Lucas Toshio Ito, Nakao Iwata, Ian Jones, Lisa Jones, Lina Jonsson, Erik G. Jönsson, René S. Kahn, Robert Karlsson, Milissa L. Kaufman, John R. Kelsoe, James L. Kennedy, Anthony P. King, Tilo Kircher, George Kirov, Per M. Knappskog, James A. Knowles, Nene Kobayashi, Karestan C. Koenen, Bettina Konte, Mayuresh S. Korgaonkar, Kaarina Kowalec, Marie‐Odile Krebs, Mikael Landén, Claudine Laurent‐Levinson, Lauren A. M. Lebois, Doug Levinson, Cathryn M. Lewis, Qingqin S. Li, Israel Liberzon, Greg Light, Sandra K. Loo, Yi Lu, Susanne Lucae, Charles R. Marmar, Nick Martin, Fermín Mayoral, Andrew M. McIntosh, Katie A. McLaughlin, Samuel A. McLean, Andrew McQuillin, Sarah E. Medland, Andreas Meyer‐Lindenberg, Vihra Milanova, Philip B. Mitchell, Esther Molina, Bryan Mowry, Bertram Müller‐Myhsok, Niamh Mullins, Robin Murray, Markus M. Nöthen, John I. Nürnberger, Kevin S. O’Connell, Roel A. Ophoff, Holly K. Orcutt, Michael J. Owen, Aarno Palotie, Carlos N. Pato, Michele T. Pato, Joanna Pawlak, Triinu Peters, Tracey L. Petryshen, Giorgio Pistis, James B. Potash, John Powell, Martin Preisig, Digby Quested, Josep Antoni Ramos‐Quiroga, Andreas Reif, Kerry J. Ressler, Marta Ribasés, Marcella Rietschel, Victoria B. Risbrough, Margarita Rivera, Alex O. Rothbaum, Barbara O. Rothbaum, Dan Rujescu, Takeo Saito, Alan R. Sanders, Russell Schachar, Peter R. Schofield, Eva C. Schulte, Thomas G. Schulze, Laura J. Scott, Soraya Seedat, Christina M. Sheerin, Jianxin Shi, Pamela Sklar, Susan L. Smalley, Olav B. Smeland, Jordan W. Smoller, Edmund Sonuga‐Barke, David St Clair, Nils Eiel Steen, Dan J. Stein, Frederike Stein, Murray B. Stein, Fabian Streit, Neal R. Swerdlow, Florence Thibaut, Johan H. Thygesen, И. Ф. Тимербулатов, Claudio Toma, Edward Trapido, Micheline Tremblay, Ming T. Tsuang, Monica Uddin, Marquis P. Vawter, John B. Vincent, Henry Völzke, James Walters, Cynthia Shannon Weickert, Lauren A. Weiss, Myrna M. Weissman, Thomas Werge, Stephanie H. Witt, Miguel Xavier, Robert H. Yolken, Ross McD. Young, Tetyana Zayats, Lori A. Zoellner, Kimberley Kendall, Brien P. Riley, Naomi R. Wray, Michael O‘Donovan, Patrick F. Sullivan, Sandra Sanchez‐Roige, Caroline M. Nievergelt, Sébastien Jacquemont, Stephen W. Scherer, Jonathan Sebat · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.07.11.25331381 · 被引用次数：5 · 研究领域：Genetic Associations and Epidemiology、Genomics and Rare Diseases、Bioinformatics and Genomic Networks

Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits b...