id_1016. ASSOCIATIONS OF GLUCOCORTICOID RECEPTOR–DEPENDENT GENE SIGNATURES WITH NEUROPSYCHIATRIC PHENOTYPES
Mateusz Zięba1, Magdalena Ziemiańska2, Małgorzata Borczyk1, Marcin Piechota1, Michał Korostyński1
1 Laboratory of Pharmacogenomics, Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
2 Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
INTRODUCTION: Stress induces the hypothalamic–pituitary–adrenal (HPA) axis, leading to glucocorticoid release. These hormones signal through the glucocorticoid receptor (GR), which regulates genes involved in metabolism, immunity, and brain function. Prolonged HPA activity disrupts GR signaling, a hallmark of stress-related psychiatric disorders. However, GR-dependent gene expression regulation remains insufficiently characterized in the context of mental health.
AIM(S): Our study aims to evaluate the genetic overlap between systemic and tissue-specific GR-dependent signatures and genes previously associated with mental health disorders.
METHOD(S): We compiled a GR-dependent gene database from 47 publications, including 13,207 protein-coding genes. From this resource, we derived systemic and tissue-specific GR signatures across neural, blood, and lung tissues, stratified by direction of regulation. The signatures were tested for genetic overlap with mental health–associated gene sets from DisGeNET, GWAS Catalog, and GeneBass. Phenotypes were mapped to ICD-10 codes from mental and behavioural disorders. We analyzed 239 phenotypes (≥10 genes) using χ² gene-overlap tests; significance was defined as p < 0.05 and ≥3 overlapping genes.
RESULTS: We identified 388 GR-dependent genes significantly associated with 51 mental health phenotypes, most frequently linked to mood (affective) disorders (n = 23). Notably, the direction of GR regulation differed between tissues: in the lung, associations were driven mainly by GR-repressed genes (p = 0.02), whereas in neural tissue, they were stronger for GR-activated genes (p = 0.04).
CONCLUSIONS: Together, these results indicate distinct central and peripheral roles of GR signaling in mental health. Neural associations are primarily driven by GR-activated genes enriched in synaptic and stress-response pathways, whereas lung associations involve GR-repressed genes linked to cytokine regulation.
FINANCIAL SUPPORT: This work was funded by NCN, Poland OPUS 23 2022/45/B/NZ5/03188.