Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels in order to test for associations with maternal stress and newborn birthweight. Maternal venous blood and newborn cord blood were assayed for methylation at ~450,000 CpG sites (n = 24 and 22, respectively). Methylation was analyzed by examining CpG sites individually (epigenome-wide-association-study [EWAS]), as regional groups (variably methylated region [VMR] analysis in maternal blood only), and through epigenome-wide measures (genome-wide mean methylation [GMM], Horvath’s epigenetic clock, and mitotic age). These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birthweight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birthweight (p-value < 1.95x10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birthweight in either maternal or cord blood after Bonferroni multiple testing correction, although the top ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p-value = 1.95x10-7 and 8.3x10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p-value 0.025) and suggestively associated with sexual violence (p-value = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birthweight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues, specifically a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we only found associations when CpG sites were analyzed in aggregate, either as variably methylation regions (VMRs) or a broad summary measure of genome-wide mean methylation (GMM).
Clukay, Christopher J.; Hughes, David A.; Kertes, Darlene A.; and Mulligan, Connie J., "Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birthweight Identified by Investigating Methylation at Individual, Regional, and Genome Levels" (2020). Human Biology Open Access Pre-Prints. 164.