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Background: Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment., Methods: Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children ( N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses., Results: Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions ( p < 1.06 × 10 -07 ), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22 , TAPBP , ZBTB12 , and DOCK4 ., Conclusions: These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

While previous studies suggest that both genetic and environmental factors play an important role in the development of autism-related traits, little is known about potential biological mechanisms underlying these associations. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined prospective associations between DNA methylation (DNAm: n birth = 804, n age 7 = 877) and trajectories of social communication deficits at age 8-17 years. Methylomic variation at three loci across the genome (false discovery rate = 0.048) differentiated children following high ( n = 80) versus low ( n = 724) trajectories of social communication deficits. This differential DNAm was specific to the neonatal period and not observed at 7 years of age. Associations between DNAm and trajectory membership remained robust after controlling for co-occurring mental health problems (i.e., hyperactivity/inattention, conduct problems). The three loci identified at birth were not replicated in the Generation R Study. However, to the best of our knowledge, ALSPAC is the only study to date that is prospective enough to examine DNAm in relation to longitudinal trajectories of social communication deficits from childhood to adolescence. Although the present findings might point to potentially novel sites that differentiate between a high versus low trajectory of social communication deficits, the results should be considered tentative until further replicated.

Epigenetic changes represent a potential mechanism underlying associations of early-life exposures and later life health outcomes. Population-based cohort studies starting in early life are an attractive framework to study the role of such changes. DNA methylation is the most studied epigenetic mechanism in population research. We discuss the application of DNA methylation in early-life population studies, some recent findings, key challenges and recommendations for future research. Studies into DNA methylation within the Developmental Origins of Health and Disease framework generally either explore associations between prenatal exposures and offspring DNA methylation or associations between offspring DNA methylation in early life and later health outcomes. Only a few studies to date have integrated prospective exposure, epigenetic and phenotypic data in order to explicitly test the role of DNA methylation as a potential biological mediator of environmental effects on health outcomes. Population epigenetics is an emerging field which has challenges in terms of methodology and interpretation of the data. Key challenges include tissue specificity, cell type adjustment, issues of power and comparability of findings, genetic influences, and exploring causality and functional consequences. Ongoing studies are working on addressing these issues. Large collaborative efforts of prospective cohorts are emerging, with clear benefits in terms of optimizing power and use of resources, and in advancing methodology. In the future, multidisciplinary approaches, within and beyond longitudinal birth and preconception cohorts will advance this complex, but highly promising, the field of research.

In 785 mother-child (50% male) pairs from a longitudinal epidemiological birth cohort, we investigated associations between inflammation-related epigenetic polygenic risk scores (i-ePGS), environmental exposures, cognitive function, and child and adolescent internalizing and externalizing problems. We examined prenatal and postnatal effects. For externalizing problems, one prenatal effect was found: i-ePGS at birth associated with higher externalizing problems (ages 7-15) indirectly through lower cognitive function (age 7). For internalizing problems, we identified two effects. For a prenatal effect, i-ePGS at birth associated with higher internalizing symptoms via continuity in i-ePGS at age 7. For a postnatal effect, higher postnatal adversity exposure (birth through age 7) associated with higher internalizing problems (ages 7-15) via higher i-ePGS (age 7). Hence, externalizing problems were related mainly to prenatal effects involving lower cognitive function, whereas internalizing problems appeared related to both prenatal and postnatal effects. The present study supports a link between i-ePGS and child and adolescent mental health.

Early-onset conduct problems (CP) are a key predictor of adult criminality and poor mental health. While previous studies suggest that both genetic and environmental risks play an important role in the development of early-onset CP, little is known about potential biological processes underlying these associations. In this study, we examined prospective associations between DNA methylation (cord blood at birth) and trajectories of CP (4-13 years), using data drawn from the Avon Longitudinal Study of Parents and Children. Methylomic variation at seven loci across the genome (false discovery rate < 0.05) differentiated children who go on to develop early-onset (n = 174) versus low (n = 86) CP, including sites in the vicinity of the monoglyceride lipase (MGLL) gene (involved in endocannabinoid signaling and pain perception). Subthreshold associations in the vicinity of three candidate genes for CP (monoamine oxidase A [MAOA], brain-derived neurotrophic factor [BDNF], and FK506 binding protein 5 [FKBP5]) were also identified. Within the early-onset CP group, methylation levels of the identified sites did not distinguish children who will go on to persist versus desist in CP behavior over time. Overall, we found that several of the identified sites correlated with prenatal exposures, and none were linked to known genetic methylation quantitative trait loci. Findings contribute to a better understanding of epigenetic patterns associated with early-onset CP.

Emerging research in epigenetics has shown that there is variability in how environmental exposures "get under the skin" through mechanisms like DNA methylation to influence gene expression that may lead to differential adaptations to stress. This is the first study to examine prospectively the relationship between DNA methylation at birth and resilience to prenatal environmental stressors in several domains (conduct, hyperactivity, emotional problems, and global symptomatology) in middle childhood. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously associated with impairments in social-cognitive processes that may underlie a wide range of childhood psychopathology. Participants were 91 youth exposed to pre- and postnatal adversity with established conduct problem trajectories drawn from the Avon Longitudinal Study of Parents and Children. Consistent with our hypothesis, OXTR DNA methylation was predictive of resilience in the conduct problems domain in middle childhood. DNA methylation profiles did not predict resilience in domains of emotional, hyperactivity, and global symptomatology, suggesting a potential role for OXTR in the development of conduct problems in particular. However, individuals who were resilient to conduct problems were also broadly resilient across multiple domains. Therefore, future research should elucidate the biological pathways between OXTR DNA methylation and gene expression and its relation to impairments in social behavior.