Background: Glucocorticoids play a crucial role as mediators of negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates the impact of genetic variants and glucocorticoid receptor (GR)-activation on gene expression and DNA methylation in peripheral blood and the relationship of these variants with disease risk. Methods: We conducted a comprehensive molecular quantitative trait locus (QTL) analysis, mapping GR-methylation (me)QTLs, GR-expression (e)QTLs, and GR-expression quantitative trait methylation (eQTM) in a cohort of 199 individuals, with DNA methylation and RNA expression data collected before and after GR-activation with dexamethasone. A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation. Results: We identified 3,772 GR-meQTL CpGs corresponding to 114,134 local GR-meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on RNA expression and DNA methylation. Multi-level network analysis uncovered GR-network trio QTLs, characterised by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. These trios' genes demonstrated enrichment in immune response and cell activation pathways and showed a significant overlap with transcripts altered by GR-activation in the mouse brain. GR-trio variants were enriched in GWAS for bipolar disorder, schizophrenia, autoimmune and cardiovascular diseases and traits, cytokines levels and BMI. Conclusions: Genetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases. Our findings support stress as a shared risk factor for transdiagnostic negative health outcomes and may lead to innovative interventions targeting shared underlying molecular mechanisms.

The authors have declared no competing interest.

This work was supported by European Union's EU Framework Programme for Research and Innovation Horizon 2020, Grant Agreement No 860895, European Training Network grant, Precision Medicine at the Interface of Translational Research and Systems Biology (TranSYS) and European Research Council (ERC) starting grant ERC starting grant number 281338 Gene x environment interactions in affective disorders - elucidating molecular mechanisms (GxE molmech) to Elisabeth Binder. Dr. Knauer-Arloth's contributions were supported by the Brain & Behavior Research Foundation (NARSAD Young Investigator Grant, #28063).

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The study was approved by the ethics board of the Ludwig Maximilians University (approval #244/01) and was conducted in accordance with the current version of the Declaration of Helsinki.

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All computational code has been made available on GitHub: https://github.com/cellmapslab/dex-stim-human-dna-methyl-qc, while the DNA methylation data are accessible in the GEO repository under GEO: GSE249113.