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

• Verfasst von: Worf, Karolina [VerfasserIn]
• Verfasst von: Matosin, Natalie [VerfasserIn]
• Verfasst von: Gerstner, Nathalie [VerfasserIn]
• Verfasst von: Fröhlich, Anna S. [VerfasserIn]
• Verfasst von: Koller, Anna C. [VerfasserIn]
• Verfasst von: Degenhardt, Franziska [VerfasserIn]
• Verfasst von: Thiele, Holger [VerfasserIn]
• Verfasst von: Rietschel, Marcella [VerfasserIn]
• Verfasst von: Udawela, Madhara [VerfasserIn]
• Verfasst von: Scarr, Elizabeth [VerfasserIn]
• Verfasst von: Dean, Brian [VerfasserIn]
• Verfasst von: Theis, Fabian J. [VerfasserIn]
• Verfasst von: Mueller, Nikola S. [VerfasserIn]
• Verfasst von: Knauer-Arloth, Janine [VerfasserIn]
• Titel: Exon-variant interplay and multi-modal evidence identify endocrine dysregulation in severe psychiatric disorders impacting excitatory neurons
• Verf.angabe: 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
• E-Jahr: 2025
• Jahr: 19 April 2025
• Umfang: 13 S.
• Illustrationen: Illustrationen, Diagramme
• Fussnoten: Gesehen am 01.07.2025
• Titel Quelle: Enthalten in: Translational Psychiatry
• Ort Quelle: London : Nature Publishing Group, 2011
• Jahr Quelle: 2025
• Band/Heft Quelle: 15(2025), Artikel-ID 153, Seite 1-13
• ISSN Quelle: 2158-3188
• DOI: doi:10.1038/s41398-025-03366-8
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Medical genetics
• Sach-SW: Molecular neuroscience
• Sach-SW: Personalized medicine
• Sach-SW: Predictive markers
• Sach-SW: Psychiatric disorders
• K10plus-PPN: 1929418337

Abstract

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.