| Title: |
Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects |
| Authors: |
Engchuan, Worrawat; Shanta, Omar; Kumar, Kuldeep; MacDonald, Jeffrey R.; Thiruvahindrapuram, Bhooma; Hamdan, Omar; Klein, Marieke; Maihofer, Adam; Guevara, James; Hong, Oanh; Huguet, Guillaume; Sacks, Molly; Ahangari, Mohammad; Feitosa, Rayssa M. M. W.; Han, Kara; Mendes, Marla; Zhou, Xiaopu; Bautista, Nelson X.; Pellecchia, Giovanna; Wang, Zhouzhi; Merico, Daniele; Yuen, Ryan K. C.; Trost, Brett; Sønderby, Ida; Adams, Mark J.; Adolfsson, Rolf; Agartz, Ingrid; Aiello, Allison E.; Alda, Martin; Allardyce, Judith; Amstadter, Ananda B.; Andlauer, Till F. M.; Andreassen, Ole A.; Artigas, María S.; Austin, S. Bryn; Ayub, Muhammad; Baker, Dewleen G.; Bass, Nick; Baune, Bernhard T.; Bayas, Maximilian; Berger, Klaus; Biernacka, Joanna M.; Bigdeli, Tim; Bisson, Jonathan I.; Blackwood, Douglas; Boks, Marco; Braff, David; Bramon, Elvira; Breen, Gerome; Brueckl, Tanja; Bryant, Richard A.; Bulik, Cynthia M.; Buxbaum, Joseph; Cairns, Murray J.; Caldas-de-Almeida, Jose M.; Campbell, Megan; Campion, Dominique; Carr, Vaughan J.; Castelao, Enrique; Chaumette, Boris; Cichon, Sven; Cohen, David; Corvin, Aiden; Craddock, Nicholas; Crosbie, Jennifer; Czamara, Darrina; Dannlowski, Udo; Degenhardt, Franziska; Delahanty, Douglas L.; Dempfle, Astrid; Desachy, Guillaume; Di Florio, Arianna; Dickerson, Faith B.; Djurovic, Srdjan; Domschke, Katharina; Douglas, Lisa; Drange, Ole K.; Duncan, Laramie E.; Edenberg, Howard J.; Esko, Tonu; Faraone, Steve; Feeny, Norah C.; Forstner, Andreas J.; Franke, Barbara; Frye, Mark; Fu, Dong-Jing; Fullerton, Janice M.; Gareeva, Anna; Garvert, Linda; Gatt, Justine M.; Gejman, Pablo; Geschwind, Daniel H.; Giegling, Ina; Glatt, Stephen J.; Glessner, Joe; Goes, Fernando S.; Gordon-Smith, Katherine; Grabe, Hans; Green, Melissa J.; Green, Michael F.; Greenwood, Tiffany; Grigoroiu-Serbanescu, Maria; Gur, Raquel E.; Gur, Ruben C.; Guzman-Parra, Jose; Haavik, Jan; Hahn, Tim; Hakonarson, Hakon; Hallmayer, Joachim; Hamshere, Marian L.; Hartmann, Annette M.; Hassan, Arsalan; Hayward, Caroline; Hebebrand, Johannes; Hemmings, Sian M. J.; Herms, Stefan; Herrera-Rivero, Marisol; Hinney, Anke; Homuth, Georg; Ingason, Andrés; Ito, Lucas T.; Iwata, Nakao; Jones, Ian; Jones, Lisa A.; Jonsson, Lina; Jönsson, Erik G.; Kahn, René S.; Karlsson, Robert; Kaufman, Milissa L.; Kelsoe, John R.; Kennedy, James L.; King, Anthony; Kircher, Tilo; Kirov, George; Knappskog, Per; Knowles, James A.; Kobayashi, Nene; Koenen, Karestan C.; Konte, Bettina; Korgaonkar, Mayuresh; Kowalec, Kaarina; Krebs, Marie-Odile; Landén, Mikael; Laurent-Levinson, Claudine; Lebois, Lauren A.; Levinson, Doug; Lewis, Cathryn; Li, Qingqin; Liberzon, Israel; Light, Greg; Loo, Sandra K.; Lu, Yi; Lucae, Susanne; Marmar, Charles; Martin, Nicholas G.; Mayoral, Fermin; McIntosh, Andrew M.; McLaughlin, Katie A.; McLean, Samuel A.; McQuillin, Andrew; Medland, Sarah E.; Meyer-Lindenberg, Andreas; Milanova, Vihra; Mitchell, Philip B.; Molina, Esther; Mowry, Bryan; Muller-Myhsok, Bertram; Mullins, Niamh; Murray, Robin; Nöthen, Markus M.; Nurnberger, John I., Jr.; O'Connell, Kevin S.; Ophoff, Roel A.; Orcutt, Holly K.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos; Pato, Michele; Pawlak, Joanna; Peters, Triinu; Petryshen, Tracey L.; Pistis, Giorgio; Potash, James B.; Powell, John; Preisig, Martin; Quested, Digby; Ramos-Quiroga, Josep A.; Reif, Andreas; Ressler, Kerry J.; Ribasés, Marta; Rietschel, Marcella; Risbrough, Victoria B.; Rivera, Margarita; Rothbaum, Alex O.; Rothbaum, Barbara O.; Rujescu, Dan; Saito, Takeo; Sanders, Alan R.; Schachar, Russell J.; Schofield, Peter R.; Schulte, Eva C.; Schulze, Thomas G.; Scott, Laura J.; Seedat, Soraya; Sheerin, Christina; Shi, Jianxin; Sklar, Pamela; Smalley, Susan; Smeland, Olav B.; Smoller, Jordan W.; Sonuga-Barke, Edmund; St. Clair, David; Steen, Nils Eiel; Stein, Dan; Stein, Frederike; Stein, Murray B.; Streit, Fabian; Swerdlow, Neal; Thibaut, Florence; Thygesen, Johan H.; Timerbulatov, Ilgiz; Toma, Claudio; Trapido, Edward; Tremblay, Micheline; Tsuang, Ming T.; Uddin, Monica; Vawter, Marquis P.; Vincent, John B.; Völzke, Henry; Walters, James T.; Weickert, Cynthia S.; Weiss, Lauren A.; Weissman, Myrna M.; Werge, Thomas; Witt, Stephanie H.; Xavier, Miguel; Yolken, Robert; Young, Ross M.; Zayats, Tetyana; Zoellner, Lori A.; 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; Kendall, Kimberley; Riley, Brien; Wray, Naomi R.; O'Donovan, Michael C.; Sullivan, Patrick F.; Sanchez-Roige, Sandra; Nievergelt, Caroline M.; Jacquemont, Sébastien; Scherer, Stephen W.; Sebat, Jonathan |
| Contributors: |
Biochemistry and Molecular Biology, School of Medicine |
| Source: |
PMC |
| Publisher Information: |
medRxiv |
| Publication Year: |
2025 |
| Collection: |
Indiana University - Purdue University Indianapolis: IUPUI Scholar Works |
| Subject Terms: |
Psychiatric conditions; Genes; Gene-set burden analysis (GSBA); Copy number variants (CNVs) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Engchuan W, Shanta O, Kumar K, et al. Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects. Preprint. medRxiv. 2025;2025.07.11.25331381. Published 2025 Jul 16. doi:10.1101/2025.07.11.25331381; https://hdl.handle.net/1805/50859 |
| Availability: |
https://hdl.handle.net/1805/50859 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.48EC7CA0 |
| Database: |
BASE |