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Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

ObjectiveWomen exposed to childhood maltreatment (CM) are more likely to exhibit insensitive parenting, which may have consequences for their offspring's development. Variation in the oxytocin-receptor gene (OXTR) moderates risk of CM-associated long-term sequelae associated with mother-child attachment, although functionality of previously investigated single nucleotide polymorphisms (SNPs) remained elusive. Here, we investigated the role of OXTR rs237895, a brain tissue expression quantitative trait locus (eQTL), as a moderator of the relationship between CM and maternal behavior (MB) and the association between MB and offspring attachment security.MethodOf 110 women with information on rs237895 genotype (T-allele = 64, CC = 46), 107 had information on CM (CTQ) and 99 on standardized observer-based ratings of MB at 6 months postpartum (responsivity and detachment), which were used in principal component analysis to obtain a latent factor representing MB. Offspring (n = 86) attachment was evaluated at 12 months of age. Analyses predicting MB were adjusted for socioeconomic status, age, postpartum depression, and genotype-based ethnicity. Analyses predicting child attachment were adjusted for infant sex, socioeconomic status, and postpartum depression.Resultsrs237895 significantly moderated the relationship between CM and MB (F1;66 = 7.99, p < .01), indicating that CM was associated with maternal insensitivity only in high-OXTR-expressing T-allele carriers but not in low-OXTR-expressing CC homozygotes. Moreover, maternal insensitivity predicted offspring insecure attachment (B = -0.551; p < .05).ConclusionWomen with a high OXTR expressing genotype are more susceptible to CM-related impairments in MB that, in turn, predict attachment security in their children, supporting the role of the OT system in the intergenerational transmission of risk associated with maternal CM.

Maternal behavior (MB) is observable across mammals and represents an important feature of environmental variation during early postnatal development. Oxytocin (OT) plays a crucial role in MB. Even prior to childbirth, pregnancy induces epigenetic and other downstream changes in the maternal OT-system, likely mediated by the actions of steroid hormones. However, little is known about the nature and consequences of epigenetic modifications in the maternal OT-encoding gene (OXT) during pregnancy. Our study aims to investigate temporal dynamics of OXT promoter DNA methylation (DNAm) throughout pregnancy in predicting MB in humans. In 107 mother-child dyads, maternal OXT DNAm was serially analyzed in whole blood in early, mid and late pregnancy. MB was coded based on standardized mother-child interactions at six months postpartum. After controlling for cellular heterogeneity, race/ethnicity, age, and socioeconomic status, OXT-promoter DNAm exhibited a dynamic profile during pregnancy (b = 0.026, t=-3.37, p

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into 4 trajectories over HPC differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting expression changes but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn’s cord blood DNA. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life. [ABSTRACT FROM AUTHOR]

Early-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by “epigenetic” mechanisms. Studies in rodents suggest a causal relationship between early-life adversity and changes in DNA methylation in several “candidate genes” in the brain. This study examines whether randomized differential rearing (maternal vs surrogate–peer rearing) of rhesus macaques is associated with differential methylation in early adulthood. The data presented here show that differential rearing leads to differential DNA methylation in both prefrontal cortex and T cells. These differentially methylated promoters tend to cluster by both chromosomal region and gene function. The broad impact of maternal rearing on DNA methylation in both the brain and T cells supports the hypothesis that the response to early-life adversity is system-wide and genome-wide and persists to adulthood. Our data also point to the feasibility of studying the impact of the social environment in peripheral T-cell DNA methylation. [ABSTRACT FROM AUTHOR]

The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. [ABSTRACT FROM AUTHOR]