Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

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 (GxCA) 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 GxCA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with GxCA interactions explaining most variance. The consistent GxCA 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.Peer reviewe

Alterations in DNA Methylation and Hydroxymethylation Due to Parental Care in Rhesus Macaques

Early life is one of the most important and sensitive periods during the development of an individual. During this stage, the body and especially the brain are known to be greatly responsive to environmental cues, such as the early social environment. As a consequence, early life adverse social experiences in humans are associated with a wide range of health problems in adulthood. The broad range of phenotypes associated with early life stress (ELS) suggests a system-wide response of the organism, which is yet to be determined. In the last decade, increasing evidence suggests that epigenetic mechanisms underlie the effects of ELS on adult human health. However, there are critical challenges in delineating the direct effects of ELS on epigenetic profiles and phenotypes in human studies. It is impossible to randomize ELS and rare are the studies where complete information about past environmental insults is available, which would allow us to conclude on causality. Nonhuman primates offer several advantages in addressing these challenges. This chapter focuses on parental deprivation models in rhesus macaques which have been shown to produce an array of behavioral, physiological, and neurobiological deficits that parallel those identified in humans subjected to ELS. It describes the evidence for epigenetic alterations induced by differential rearing in this model and points out the differences between tissue-specific versus multi-tissue changes and outlines possible mechanisms for these to occur. In addition, it highlights the need for multi-omics longitudinal studies to better understand the epigenetic trajectories induced by ELS exposure and their impact on adult health