Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy

Abstract

Maternal depressive symptoms during pregnancy are a significant risk factor for adverse developmental and health outcomes of the offspring. The molecular mechanisms mediating the long-term effects of this exposure are not well understood. Previous studies have found association between prenatal exposure to maternal psychological distress and placental DNA methylation of candidate genes, which can influence placental barrier function and development of the fetus. Our objective in this study was to determine epigenome wide association of maternal depressive symptoms in early pregnancy with the placental DNA methylation. For this purpose we examined DNA methylomes of 92 placental samples by using reduced representation bisulfite sequencing. The placental samples were collected after deliveries of 39 girls and 59 boys, whose mothers had Edinburgh Postnatal Depression Score ranging from 0 to 19 at gestational week 14. According to our results maternal depressive symptoms are associated with DNA methylation of 2833 CpG sites, which are particularly over-represented in genic enhancers. The genes overlapping or nearest to these sites are functionally enriched for development of neurons and show expression enrichment in several regions of developing brain. The genomic regions harboring the DNA methylation marks are enriched for single nucleotide polymorphisms associated with mental disease trait class. Potential cellular signaling cascades mediating the effects include inflammatory and hormonal pathways. As a conclusion our results suggest that maternal depressive symptoms during early pregnancy are associated with DNA methylation marks in placenta in genes, which are important for the development and long-term health of the brain. Whether similar marks can be detected in exposed children remains to be elucidated in further studies.

The Placental Epigenome as a Molecular Link Between Prenatal Exposures and Fetal Health Outcomes Through the DOHaD Hypothesis

“…In a subset of 581 individuals from the RICHS cohort, 21 imprinted DEGs were associated with maternal depression and anxiety, and 5 imprinted DEGs associated with depression alone, with no differential gene expression in the anxiety only group [ 44 ]. Differential methylation at 2833 CpG sites (FDR < 0.05) was associated with maternal depression at 14 weeks in the FinnBrain Birth Cohort Study ( N = 92) [ 45 ]. Genes closest to these CpG sites were enriched in pathways involving generation and development of neurons [ 45 ].…”

“…Differential methylation at 2833 CpG sites (FDR < 0.05) was associated with maternal depression at 14 weeks in the FinnBrain Birth Cohort Study ( N = 92) [ 45 ]. Genes closest to these CpG sites were enriched in pathways involving generation and development of neurons [ 45 ]. Across these two studies of maternal depression, the gene Erlin2 was identified as a differentially expressed imprinted gene by Litzky et al and as being adjacent to four differentially methylated CpG sites by Lund et al [ 44 , 45 ].…”

“…Genes closest to these CpG sites were enriched in pathways involving generation and development of neurons [ 45 ]. Across these two studies of maternal depression, the gene Erlin2 was identified as a differentially expressed imprinted gene by Litzky et al and as being adjacent to four differentially methylated CpG sites by Lund et al [ 44 , 45 ]. Although a placental specific role for this gene is unknown, its protein is known to be localized to the endoplasmic reticulum where it has functions in protein degradation and lipid metabolism [ 56 ].…”

From the Womb into the World: Protecting the Fetal Brain from Maternal Stress During Pregnancy

“…Furthermore, epigenetic modifications may also alter fetal gene expression in interaction with other mechanisms; for example, via altering placental functioning (Monk, Spicer, et al, 2012b). Reported epigenetic changes of the placenta emerged in mothers suffering from psychological stress (e.g., Capron et al, 2018; Jensen Peña et al, 2012; Lund et al, 2021).…”

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation

“…Contrastingly, a meta-analysis of two epidemiological cohorts of predominantly European ancestry found no sign cant associations between prenatal stressful life events and DNA methylation in cord blood 33 . Other agnostic EWASes examining associations with prenatal perceived maternal stress and cord blood DNA methylation 34 or maternal depression during pregnancy and placental DNA methylation 35,36 , also report mixed results. Given the con icting nature of these studies, likely due to population characteristics and/or choice of tissue, there is a need to conduct larger-scaled meta-analyses to increase power, include populations from different genetic ancestries, as well as cultural settings with different levels of maternal stressful life events, and utilize a single tissue sample source for comparison .…”