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

Worrawat Engchuan, Omar Shanta, Kuldeep Kumar, Jeffrey R MacDonald, Bhooma Thiruvahindrapuram, Omar Hamdan, Marieke Klein, Adam Maihofer, James Guevara, Oanh Hong, Guillaume Huguet, Molly Sacks, Mohammad Ahangari, Rayssa M M W Feitosa, Kara Han, Marla Mendes, Xiaopu Zhou, Nelson X Bautista, Giovanna Pellecchia, Zhouzhi Wang, Daniele Merico, Ryan K C Yuen, Brett Trost, Ida 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 Bigdeli, Jonathan I Bisson, Douglas Blackwood, Marco Boks, David Braff, Elvira Bramon, Gerome Breen, Tanja Brueckl, Richard A Bryant, Cynthia M Bulik, Joseph Buxbaum, Murray J Cairns, Jose M Caldas-de-Almeida, Megan Campbell, Dominique Campion, Vaughan J Carr, Enrique Castelao, Boris Chaumette, Sven Cichon, David Cohen, Aiden Corvin, Nicholas Craddock, Jennifer Crosbie, Darrina Czamara, Udo Dannlowski, Franziska Degenhardt, Douglas L Delahanty, Astrid Dempfle, Guillaume Desachy, Arianna Di Florio, Faith B Dickerson, Srdjan Djurovic, Katharina Domschke, Lisa Douglas, Ole K Drange, Laramie E Duncan, Howard J Edenberg, Tonu Esko, Steve Faraone, Norah C Feeny, Andreas J Forstner, Barbara Franke, Mark Frye, Dong-Jing Fu, Janice M Fullerton, Anna Gareeva, Linda Garvert, Justine M Gatt, Pablo Gejman, Daniel H Geschwind, Ina Giegling, Stephen J Glatt, Joe Glessner, Fernando S Goes, Katherine Gordon-Smith, Hans Grabe, Melissa J Green, Michael F Green, Tiffany Greenwood, Maria Grigoroiu-Serbanescu, Raquel E Gur, Ruben C Gur, Jose Guzman-Parra, Jan Haavik, Tim Hahn, Hakon Hakonarson, Joachim Hallmayer, Marian L Hamshere, Annette M Hartmann, Arsalan Hassan, Caroline Hayward, Johannes Hebebrand, Sian M J Hemmings, Stefan Herms, Marisol Herrera-Rivero, Anke Hinney, Georg Homuth, Andrés Ingason, Lucas T Ito, Nakao Iwata, Ian Jones, Lisa A Jones, Lina Jonsson, Erik G Jönsson, René S Kahn, Robert Karlsson, Milissa L Kaufman, John R Kelsoe, James L Kennedy, Anthony King, Tilo Kircher, George Kirov, Per Knappskog, James A Knowles, Nene Kobayashi, Karestan C Koenen, Bettina Konte, Mayuresh Korgaonkar, Kaarina Kowalec, Marie-Odile Krebs, Mikael Landén, Claudine Laurent-Levinson, Lauren A Lebois, Doug Levinson, Cathryn Lewis, Qingqin Li, Israel Liberzon, Greg Light, Sandra K Loo, Yi Lu, Susanne Lucae, Charles Marmar, Nicholas G Martin, Fermin 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 Muller-Myhsok, Niamh Mullins, Robin Murray, Markus M Nöthen, John I Nurnberger, Kevin S O'Connell, Roel A Ophoff, Holly K Orcutt, Michael J Owen, Aarno Palotie, Carlos Pato, Michele Pato, Joanna Pawlak, Triinu Peters, Tracey L Petryshen, Giorgio Pistis, James B Potash, John Powell, Martin Preisig, Digby Quested, Josep A 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 J Schachar, Peter R Schofield, Eva C Schulte, Thomas G Schulze, Laura J Scott, Soraya Seedat, Christina Sheerin, Jianxin Shi, Pamela Sklar, Susan Smalley, Olav B Smeland, Jordan W Smoller, Edmund Sonuga-Barke, David St Clair, Nils Eiel Steen, Dan Stein, Frederike Stein, Murray B Stein, Fabian Streit, Neal Swerdlow, Florence Thibaut, Johan H Thygesen, Ilgiz Timerbulatov, Claudio Toma, Edward Trapido, Micheline Tremblay, Ming T Tsuang, Monica Uddin, Marquis P Vawter, John B Vincent, Henry Völzke, James T Walters, Cynthia S Weickert, Lauren A Weiss, Myrna M Weissman, Thomas Werge, Stephanie H Witt, Miguel Xavier, Robert Yolken, Ross M Young, Tetyana Zayats, Lori A Zoellner, AGP Consortium, PEIC Psychosis Endophenotypes International Consortium, ADHD Working Group of the Psychiatric Genomics Consortium, Autism Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, PTSD Working Group of the Psychiatric Genomics Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, CNV Working Group of the Psychiatric Genomics Consortium, Kimberley Kendall, Brien Riley, Naomi R Wray, Michael C O'Donovan, Patrick F Sullivan, Sandra Sanchez-Roige, Caroline M Nievergelt, Sébastien Jacquemont, Stephen W Scherer, Jonathan Sebat

medRxiv [Preprint]. 2025 Jul 16:2025.07.11.25331381. doi: 10.1101/2025.07.11.25331381.

ABSTRACT

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 but differ between diagnostic categories in context and directionality.

PMID:40791676 | PMC:PMC12338884 | DOI:10.1101/2025.07.11.25331381