Cover Image

Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons

Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects...

Full description

Saved in:
Bibliographic Details
Main Authors: Worf, Karolina (Author) , Matosin, Natalie (Author) , Gerstner, Nathalie (Author) , Fröhlich, Anna S. (Author) , Koller, Anna C. (Author) , Degenhardt, Franziska (Author) , Thiele, Holger (Author) , Rietschel, Marcella (Author) , Udawela, Madhara (Author) , Scarr, Elizabeth (Author) , Dean, Brian (Author) , Theis, Fabian J. (Author) , Mueller, Nikola S. (Author) , Knauer-Arloth, Janine (Author)
Format: Article (Journal)
Language:English
Published: 19 April 2025
In: Translational Psychiatry
Year: 2025, Volume: 15, Pages: 1-13
ISSN:2158-3188
DOI:10.1038/s41398-025-03366-8
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41398-025-03366-8
Verlag, kostenfrei, Volltext: http://www.nature.com/articles/s41398-025-03366-8
Get full text
Author Notes:Karolina Worf, Natalie Matosin, Nathalie Gerstner, Anna S. Fröhlich, Anna C. Koller, Franziska Degenhardt, Holger Thiele, Marcella Rietschel, Madhara Udawela, Elizabeth Scarr, Brian Dean, Fabian J. Theis, Nikola S. Mueller and Janine Knauer-Arloth
Description
Summary:Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038). Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2-6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.
Item Description:Gesehen am 01.07.2025
Physical Description:Online Resource
ISSN:2158-3188
DOI:10.1038/s41398-025-03366-8

Similar Items