Poster Presentation GENEMAPPERS 2026

Transdiagnostic impact of adversity on the orbitofrontal cortex in psychiatric disorders: a spatial and single-nucleus multi-omics approach (#58)

Tamim Ahsan 1 2 3 4 5 6 , Dominic Kaul 1 2 3 , Amber Curry 1 2 3 4 , Katrina Z Edmond 1 2 3 4 , Nathalie Gerstner 5 7 8 , Anna S Fröhlich 5 7 8 , Lezanne Ooi 4 , Elisabeth Binder 5 9 , Janine Knauer-Arloth 5 8 , Natalie Matosin 1 2 3
  1. School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia
  2. Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
  3. Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia
  4. Molecular Horizons and School of Science , University of Wollongong, Wollongong, New South Wales, Australia
  5. Department Genes and Environment, Max Planck Institute of Psychiatry, München, New South Wales, Germany
  6. Molecular Biotechnology Division, National Institute of Biotechnology , Dhaka, Bangladesh
  7. International Max Planck Research School for Translational Psychiatry, München, Germany
  8. Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
  9. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA

Adversity is a major environmental risk factor for psychiatric disorders, but its molecular consequences in the brain are incompletely understood. In this study, we examined postmortem orbitofrontal cortex (BA11) samples from 100 individuals: n=39 neurotypical controls with low adversity exposure, and n=61 major psychiatric disorder cases (schizophrenia, major depression or bipolar disorder) with high (n=28) or low (n=33) adversity exposure. We profiled the transcriptome (single-nucleus RNA sequencing) of ~800,000 nuclei and the epigenome (single-nucleus Assay for Transposase-Accessible Chromatin sequencing) of ~400,000 nuclei, along with ~45,000 spots using Visium spatial transcriptomic platform. Our analysis revealed that oligodendrocyte precursor cells (OPCs) and deeper layer (L4-6) excitatory neurons (Exc_L4-6) had the highest number of differentially expressed and/or accessible genes in high-adversity cases compared with either controls or low-adversity cases.  Notably, we observed an OPC-specific upregulation of FKBP5, a key mediator of the stress response1. Compositional analyses showed that OPCs were more abundant in high-adversity cases. Results from gene set enrichment and cell-cell communication analyses were consistent with this observation, suggesting that OPC proliferation and differentiation may be impacted due to the dysregulation of Wnt, insulin, estrogen and thyroid signalling pathways among others. Weighted gene coexpression network (WGCNA) identified a high adversity-associated gene module with GSK3β as one of its hub genes, which is associated with stress-induced psychopathology and can modulate treatment response2. In Exc_L4-6, dendrite development was impacted, possibly due to the dysregulation of its related processes such as small GTPase signalling and actin organisation. This was supported by the upregulation of EPS8L2 expression, which plays a role in actin remodelling3. Finally, the analysis of spatial transcriptomic data showed cortical layer 2/3-specific upregulation of ADCYAP1, which is associated with stress-related psychopathology4. We thus identified adversity-associated transdiagnostic candidate genes and pathways. Efforts are currently underway to validate some of the key findings.

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  2. Duda, P., Hajka, D., Wójcicka, O., Rakus, D. & Gizak, A. GSK3β: A master player in depressive disorder pathogenesis and treatment responsiveness. Cells 9, 727 (2020).
  3. Offenhäuser, N. et al. The eps8 family of proteins links growth factor stimulation to actin reorganization generating functional redundancy in the ras/rac pathway. MBoC 15, 91–98 (2004).
  4. Ressler, K. J. et al. Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470, 492–497 (2011).