Abstract
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.
Highlights
Childhood adversity (CA), including child abuse and neglect, is a major risk factors for the development of stress-related psychiatric and other medical disordersDNA methylation (DNAm) has been proposed as a biological process by which early-life adversity may have lasting effects on gene transcription providing a molecular mechanism for how early environment could influence health outcomes later in life[8,9]
We examined whether interindividual differences in DNAm levels of overlapping variably methylated probes (VMPs) were better explained by genotype in cis, by CA (E), or by additive or interaction effects of cis genotype (G) and CA together
We compared the adjusted R2 of four regression models (CA, G, G + CA, G × CA) to find the model which best explained DNAm variation in VMPs
Summary
Childhood adversity (CA), including child abuse and neglect, is a major risk factors for the development of stress-related psychiatric and other medical disordersDNA methylation (DNAm) has been proposed as a biological process by which early-life adversity may have lasting effects on gene transcription providing a molecular mechanism for how early environment could influence health outcomes later in life[8,9]. The majority of autosomal CpGs (about 80%) are not variable across tissues and individuals[11,12], leaving only about 20% of CpG sites that may contribute to differences in phenotypes and health[13]. These variable CpGs are of specific interest as they are enriched for functionally relevant genomic regions, associated with effects on gene expression[12]. The impact of genetic variation, especially of singlenucleotide polymorphisms (SNPs), on DNAm in different tissues, has been investigated in many studies and a large number of methylation quantitative trait loci (SNPs significantly associated with DNAm status14) have been discovered which are relatively stable throughout the life course[15]
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