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. 2016 Nov;28(4pt2):1385-1399.
doi: 10.1017/S0954579416000055. Epub 2016 Feb 5.

Differential DNA methylation in peripheral blood mononuclear cells in adolescents exposed to significant early but not later childhood adversity

Elisa A Esposito  1 , Meaghan J Jones  2 , Jenalee R Doom  1 , Julia L MacIsaac  2 , Megan R Gunnar  1 , Michael S Kobor  2
Affiliations

Differential DNA methylation in peripheral blood mononuclear cells in adolescents exposed to significant early but not later childhood adversity

Elisa A Esposito et al. Dev Psychopathol. 2016 Nov.

Abstract

Internationally adopted adolescents who are adopted as young children from conditions of poverty and deprivation have poorer physical and mental health outcomes than do adolescents conceived, born, and raised in the United States by families similar to those who adopt internationally. Using a sample of Russian and Eastern European adoptees to control for Caucasian race and US birth, and nonadopted offspring of well-educated and well-resourced parents to control for postadoption conditions, we hypothesized that the important differences in environments, conception to adoption, might be reflected in epigenetic patterns between groups, specifically in DNA methylation. Thus, we conducted an epigenome-wide association study to compare DNA methylation profiles at approximately 416,000 individual CpG loci from peripheral blood mononuclear cells of 50 adopted youth and 33 nonadopted youth. Adopted youth averaged 22 months at adoption, and both groups averaged 15 years at testing; thus, roughly 80% of their lives were lived in similar circumstances. Although concurrent physical health did not differ, cell-type composition predicted using the DNA methylation data revealed a striking difference in the white blood cell-type composition of the adopted and nonadopted youth. After correcting for cell type and removing invariant probes, 30 CpG sites in 19 genes were more methylated in the adopted group. We also used an exploratory functional analysis that revealed that 223 gene ontology terms, clustered in neural and developmental categories, were significantly enriched between groups.

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Figures

Figure 1
Figure 1
White blood cell type proportions differed between Adopted and Non-Adopted youth in this study but not in a previously published data set. A and B) Proportion of white blood cell types as predicted using a published algorithm are shown separated by Adopted (blue) and Non-Adopted (red) in our study (A), and a previously published study (B). Boxes are box and whisker plots of the 25th, 50th and 75th percentile. Indicated p values are the result of unpaired t tests comparing the distribution of the two groups. [(CD8T=CD8+ T cells, CD4T=CD4+ T cells, NK=natural killer cells, MONO=monocytes, GRAN=granulocytes. Note that no granulocytes were estimated because these are mononuclear cells]. C) Ratios of CD8/CD4 T cells differed between the non-adopted participants in this study and the other groups.
Figure 2
Figure 2
Blood cell type is an important and confounding factor in the analysis of DNA methylation and adoption status. On the left, heatmaps of significance between top 20 principal component scores and variables of interest. On the right, histograms of the proportion of variance accounted for in the data by the indicated principal component. A) Prior to correction for cell type, principal components were significantly associated with adoption status (Group), the covariates of interest, and all cell types. B) After correction for cell type, association with cell types is no longer present, and both significance level and proportion of variance for the Group-associated principal component has decreased. C) Density plot of uncorrected p-value distribution for linear model on 415,926 probes (red line). Left skewing indicates enrichment for very small but non-significant p values. Grey lines represent similar distributions for 100 permutations of group assignment, summarized by a mean line in black.
Figure 3
Figure 3
DNA methylation findings were supportive of higher cigarette smoke exposure in adopted participants. A) CYP1A1 was more methylated in adopted (A, blue) than non-adopted (N, red) participants at two sites as found in the EWAS analysis. B) to validate this, four CpGs in the AHRR gene were examined for differential DNA methylation between adopted and non-adopted participants. Two, cg05575912 and cg23067299 (indicated with an asterisk), were significantly differentially methylated at an FDR of 0.05.
Figure 4
Figure 4
Whole-genome EWAS found a signature of association between adoption status and DNA methylation, and functional analysis revealed many neurological and developmental processes. B) Enrichment map for GO terms significantly enriched in EWAS with an FDR<0.05 assessed by ErmineJ. Only clusters with four or more GO terms were included in this figure, and cluster names were assigned by WordCloud. GO terms are represented by nodes, node size indicates number of genes in each term and node color indicates multifunctionality score for each term. Edge width indicates number of shared genes between terms.
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