Stage 2 Registered Report: Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation

Abstract

Objective: Individual differences in risk for mental disorders over the lifespan are shaped by forces acting before the individual is born-in utero, but likely even earlier, during the mother's own childhood. The environmental epigenetics hypothesis proposes that sustained effects of environmental conditions on gene expression are mediated by epigenetic mechanisms. Recent human studies have shown that adversities in childhood are correlated with DNA methylation (DNAm) in adulthood. In the current study, we tested the following pre-registered hypotheses: Mothers' adverse childhood experiences (ACEs) are correlated with DNAm in peripheral blood during pregnancy (hypothesis 1) and in cord blood samples from newborn infants (hypothesis 2), and women's depression and anxiety symptoms during pregnancy mediate the association between mothers' ACE exposure and prenatal/neonatal DNA methylation (hypothesis 3).

Method: Data were from the Avon Longitudinal Study of Parents and Children Accessible Resource for Integrated Epigenomic Studies substudy. Women provided retrospective self-reports during pregnancy of ACE exposure. We conducted an epigenome-wide association study testing whether mothers' ACE exposure, cumulative score (0-10), was associated with DNAm in maternal antenatal blood and infant cord blood in more than 450,000 CpG (point on DNA sequence where cytosine and guanine base pairs are linked by a phosphate, where methylation usually occurs) sites on the Illumina 450K BeadChip. Analyses for cord blood were separated by infant sex, a pre-registered analysis.

Results: Hypothesis 1: In 896 mother-infant pairs with available methylation and ACE exposure data, there were no significant associations between mothers' ACE score and DNAm from antenatal peripheral blood, after controlling for covariates. Hypothesis 2: In infant cord blood, there were 5 CpG sites significantly differentially methylated in relation to mothers' ACEs (false discovery rate [FDR] < .05), but only in male offspring. Effect sizes were medium, with partial eta squared values ranging from 0.060 to 0.078. CpG sites were in genes related to mitochondrial function and neuronal development in the cerebellum. Hypothesis 3: There was no mediation by maternal anxiety/depression symptoms found between mothers' ACEs score and DNAm in the significant CpG sites in male cord blood. Mediation was not tested in antenatal peripheral blood, because no direct association between mothers' ACE score and antenatal peripheral blood was found.

Conclusion: Our results show that mothers' ACE exposure is associated with DNAm in male offspring, supporting the notion that DNAm could be a marker of intergenerational biological embedding of mothers' childhood adversity.

Study registration information: Epigenetic Intergenerational Transmission: Mothers' Adverse Childhood Experiences and DNA Methylation; https://doi.org/10.1016/j.jaac.2020.03.008.

Keywords: ALSPAC; DNA methylation; adverse childhood experiences; intergenerational transmission; longitudinal cohort.