Association between maternal perceived stress during pregnancy and offspring DNA methylation changes in HPA axis genes at birth in the ECHO Consortium

Evidence has linked maternal exposure to stress during pregnancy with poor offspring health and neurodevelopmental outcomes. However, the precise mechanism by which this may occur has not been fully elucidated. In this study, we examined whether maternal perceived stress during pregnancy was associated with newborn blood DNA methylation (DNAm) in hypothalamic-pituitary-adrenal axis-related genes (<i>NR3C1, FKBP5</i>, and <i>HSD11B2)</i> in single CpG site and gene-based analyses. We analysed a subset of 661 mother-child pairs from the Environmental Influences on Child Health Outcomes cohort study that met our analytic inclusion criteria. Maternal perceived stress was measured during pregnancy using the perceived stress scale, and newborn DNAm was measured using the Illumina 450K and EPIC Beadchips in cord blood and dried blood spots. Single-site associations were evaluated using linear regression models, and gene-based associations were evaluated using mean burden and variance component tests, adjusted for sociodemographic and lifestyle covariates. Sex-stratified models were used to evaluate sex differential effects. Prenatal perceived stress was statistically significantly associated with newborn DNAm in one CpG site (cg06613263) in <i>NR3C1</i> and with aggregate DNAm in <i>NR3C1</i> and <i>FKBP5</i>. Aggregate DNAm in <i>FKBP5</i> was more strongly associated with prenatal perceived stress in female infants. These results may have important implications for improving offspring health and well-being by providing molecular targets that can be used to identify high-risk individuals and as a basis for developing and evaluating effective behaviour and pharmaceutical interventions.