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Preprint
Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects
medRxiv , Vol.16 July 2025
Cold Spring Harbor Laboratory Press
2025
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.
Details
- Title
- Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects
- Authors
- Worrawat Engchuan - Hospital for Sick ChildrenOmar Shanta - University of California, San DiegoKuldeep Kumar - Centre Hospitalier Universitaire Sainte-JustineJeffrey R MacDonald - Hospital for Sick ChildrenBhooma Thiruvahindrapuram - Hospital for Sick ChildrenOmar Hamdan - Hospital for Sick ChildrenMarieke Klein - Radboud University NijmegenAdam X Maihofer - University of California, San DiegoJames Guevara - University of California, San DiegoOanh Hong - University of California, San DiegoSee article text for complete list of authors (Author)Ross Young - University of the Sunshine Coast, Queensland, Office of the Deputy Vice-Chancellor (Research and Innovation)
- Publication details
- medRxiv , Vol.16 July 2025
- Publisher
- Cold Spring Harbor Laboratory Press
- Date published
- 2025
- DOI
- 10.1101/2025.07.11.25331381
- Copyright note
- The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
- Grant note
- We thank the many research participants. The PGC is supported by grants to UCSD (R01MH124847), UNC (R01MH124871), MGH (R01MH124851), Mount Sinai School of Medicine (R01MH124839), Cardiff University (R01MH124873), Trinity College Dublin (R01MH124875) and Washington University St. Louis (R01DA054869). Additional support was provided by grants to J.S. (MH119746, MH133899), C.N. (MH106595, MH124847) and S.J. (U01 MH119690, U01 MH119739, CIHR_495906). Funding for the work in Bipolar Disorder was supported by the Research Council of Norway (#223273, 248778, 262656, 273291, 283798, 248828), South East Norway Health Authority (2017-112), and KG Jebsen Stiftelsen. The iPSYCH project is supported by grants from the Lundbeck Foundation (R165-2013-15320, R102-A9118, R155-2014-1724 and R248-2017-2003) and the universities and university hospitals of Aarhus and Copenhagen. Genotyping of iPSYCH samples was supported by grants from the Lundbeck Foundation, the Stanley Foundation, the Simons Foundation (SFARI 311789 to M.J.D.), and NIMH (5U01MH094432-02 to M.J.D.). The Danish National Biobank resource was supported by the Novo Nordisk Foundation. Data handling and analysis on the GenomeDK HPC facility was supported by NIMH (1U01MH109514-01 to A.D.B.). High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). Additional support to S.W.S from The University of Toronto McLaughlin Centre, the Hospital for Sick Children (SickKids) Foundation, the Ontario Brain Institute, Genome Canada/Ontario Genomics Institute and the Northbridge Chair in Paediatric Research held at the Hospital for Sick Children and University of Toronto.
- Organisation Unit
- Office of the Deputy Vice-Chancellor (Research and Innovation)
- Language
- English
- Record Identifier
- 991164945402621
- Output Type
- Preprint
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