Novel epigenetic and transcriptomic profiles of immune, inflammatory, and cellular transduction pathways are associated with chronic perceived stress in midlife women

The purpose of this exploratory analysis is to identify pathways common to both DNA methylation and gene expression linked to high perceived stress and evaluate protein-protein interactions of the genes in these pathways. To do this, we selected a sample of premenopausal healthy women stratified for being high (n = 31) and low stress (n = 32) from a large study who had available biospecimens. We used two meta-analysis approaches (strict and inclusive) to identify the pathways supported across the molecular data types, both methylation and gene expression. To delineate potential interactions among the pathways and functional roles of genes linked to the high stress group through epigenomic and transcriptomic analyses, we assessed protein-protein interaction (PPI) network connectivity utilizing the Search Tool for the Retrieval of Interacting Genes (STRING). We identified 17 KEGG pathways that were significant (p-value <0.05) and are implicated in immune response and inflammation, cellular transduction and structure, neurotransmission, and disease. The PPI network exhibits significant interconnectedness among genes, with many gene members of multiple pathways, indicating direct interactions among these pathways. Our findings help target novel stress-related biological pathways for monitoring - for timely intervention, prevention, and tailored treatment approaches. Further replicative studies in wider, diverse populations are necessary to validate the observed functional network pathways and to quantify the specificity of these pathways for duration or magnitude of perceived psychological stress.