Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders

Abstract

AbstractBackgroundGlucocorticoids 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.MethodsWe 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.ResultsWe 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.ConclusionsGenetic 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.