This study examined hostility and harsh discipline of both mothers and fathers as potential mechanisms explaining the association between a maternal maltreatment history and her offspring's internalizing and externalizing problems. Prospective data from fetal life to age 6 were collected from a total of 4,438 families participating in the Generation R Study. Maternal maltreatment was assessed during pregnancy using a self-administered questionnaire. Mothers and fathers each reported on their psychological distress and harsh discipline when the child was 3 years. Children's internalizing and externalizing problems were assessed by parental reports and child interview at age 6. Findings from structural equation modeling showed that the association between a maternal maltreatment history and her offspring's externalizing problems was explained by maternal hostility and harsh discipline and, at least partially, also by paternal hostility and harsh discipline. Child interview data provided support for both these indirect paths, with associations largely similar to those observed for parent reports.

DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for nonlinear change and inter-individual variation in nonlinear trajectories was somewhat less common (11% and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. By contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often nonlinear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.

Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.

This study aimed to establish potential mechanisms through which economic disadvantage contributes to the development of young children’s internalizing and externalizing problems. Prospective data from fetal life to age 3 years were collected in a total of 2,169 families participating in the Generation R Study. The observed physical home environment, the provision of learning materials in the home, maternal depressive symptoms, parenting stress, and harsh disciplining practices were all analyzed as potential mediators of the association between economic disadvantage and children’s internalizing and externalizing problem scores. Findings from structural equation modeling showed that for both internalizing and externalizing problems, the mechanisms underlying the effect of economic disadvantage included maternal depressive symptoms, along with parenting stress and harsh disciplining. For internalizing but not for externalizing problem scores, the lack of provision of learning materials in the home was an additional mechanism explaining the effect of economic disadvantage. The current results suggest that interventions that focus solely on raising income levels may not adequately address problems in the family processes that emerge as a result of economic disadvantage. Policies to improve the mental health of mothers with young children but also their home environments are needed to change the economic gradient in child behavior.