Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder

Abstract

Childhood maltreatment is likely to influence fundamental biological processes and engrave long-lasting epigenetic marks, leading to adverse health outcomes in adulthood. We aimed to elucidate the impact of different early environment on disease-related genome-wide gene expression and DNA methylation in peripheral blood cells in patients with posttraumatic stress disorder (PTSD). Compared with the same trauma-exposed controls (n = 108), gene-expression profiles of PTSD patients with similar clinical symptoms and matched adult trauma exposure but different childhood adverse events (n = 32 and 29) were almost completely nonoverlapping (98%). These differences on the level of individual transcripts were paralleled by the enrichment of several distinct biological networks between the groups. Moreover, these gene-expression changes were accompanied and likely mediated by changes in DNA methylation in the same loci to a much larger proportion in the childhood abuse (69%) vs. the non-child abuse-only group (34%). This study is unique in providing genome-wide evidence of distinct biological modifications in PTSD in the presence or absence of exposure to childhood abuse. The findings that nonoverlapping biological pathways seem to be affected in the two PTSD groups and that changes in DNA methylation appear to have a much greater impact in the childhood-abuse group might reflect differences in the pathophysiology of PTSD, in dependence of exposure to childhood maltreatment. These results contribute to a better understanding of the extent of influence of differences in trauma exposure on pathophysiological processes in stress-related psychiatric disorders and may have implications for personalized medicine.

Keywords: biomarkers; development; epigenome; psychiatry.

Fig. 1.

Influence of child abuse on gene expression profiles in peripheral blood in PTSD. (A) Venn diagram representing the overlap of transcripts significantly differentially regulated between individuals with PTSD and child abuse vs. trauma-exposed controls and individuals with PTSD without child abuse vs. trauma-exposed controls. (B) Heatmap of differentially expressed transcripts. Gene-expression fold-changes in comparison with the controls is depicted. Up-regulation is depicted in magenta and down-regulation is depicted in bright green.

Fig. 2.

Influence of child abuse on DNA methylation in peripheral blood in PTSD. (A) DNA methylation differences are more frequent in PTSD with child abuse. The bar graph shows the percentage of transcripts differentially regulated in the two respective group comparisons having one or more, two or more, or five or more differentially methylated CpGs in the locus. DNA methylation changes underlying the observed gene expression differences were 2- to 12-fold higher in the PTSD with child abuse group compared with the PTSD with no child abuse group. (B) Correlations of DNA methylation with gene expression. The bar graph shows the percent of CpGs with positive vs. negative correlations with gene expression of the closest transcript in the whole sample stratified by location with respect to the regulated gene. Inverse correlations close to the transcription start sites and an increasing proportion of positive correlations in proximal and distal regulatory sites were observed. (C) Distribution of the tested (left panels) and significant (middle panels) CpGs and direction of methylation across all differentially methylated CpGs in both groups. The right panels denote the relative distributions of all tested and significant CpG sites with respect to the closest gene and the CpG islands and the directions of methylation differences of the significant CpGs. Of the significant CpGs, 90% were hypermethylated and 10% were hypomethylated in the PTSD case group with respect to the controls.

Fig. 3.

Two examples of directional associations between DNA methylation and gene-expression changes. This figure shows gene-expression and DNA methylation data for two genes, DLC1 (deleted in liver cancer 1 gene) and FSCN1 (fascin homolog 1, actin-bundling protein). The position of the significant CpGs in relation to the gene, CpG islands and other CpGs on the 450 k methylation array are on top of the series of diagrams for each gene (with DLC1 on top and FSCN1 on the bottom). Below, we depict the difference in gene expression for the respective group comparison (Left), the correlation of methylation levels of a representative CpG in that locus with the expression level of the gene in the whole sample (Center), and the group differences in DNA methylation of the significant CpGs in the respective locus (Right). These data illustrate that the direction of the differences in DNA methylation and gene expression between the groups are as expected from the direction of correlation between gene expression and DNA methylation in the overall sample. * indicates adjusted P value of less than or equal to 0.05.