Epigenetic Vestiges of Early Developmental Adversity: Childhood Stress Exposure and DNA Methylation in Adolescence

University of Wisconsin School of Medicine and Public Health University of British Columbia University of Wisconsin School of Medicine and Public Health University of British Columbia.
Child Development (Impact Factor: 4.92). 09/2011; 84(1). DOI: 10.1111/j.1467-8624.2011.01641.x
Source: PubMed


Fifteen-year-old adolescents (N = 109) in a longitudinal study of child development were recruited to examine differences in DNA methylation in relation to parent reports of adversity during the adolescents' infancy and preschool periods. Microarray technology applied to 28,000 cytosine-guanine dinucleotide sites within DNA derived from buccal epithelial cells showed differential methylation among adolescents whose parents reported high levels of stress during their children's early lives. Maternal stressors in infancy and paternal stressors in the preschool years were most strongly predictive of differential methylation, and the patterning of such epigenetic marks varied by children's gender. To the authors' knowledge, this is the first report of prospective associations between adversities in early childhood and the epigenetic conformation of adolescents' genomic DNA.

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Available from: Marilyn J Essex, Oct 05, 2015
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    • "A critical issue for the study of the developmental origins of psychopathology is that of how the influences of the early environment are biologically embedded, and thus exert an enduring influence on neural function. Studies over the past decade reveal stable effects of environmental conditions, including parental " signals, " on the epigenome in brain regions associated with affective illness (Champagne, 2012; Essex et al., 2013; Heim & Binder, 2012; Labonte et al., 2012; McGowan et al., 2009; Roth & Sweatt, 2011; Zhang & Meaney, 2010). These epigenetic marks control the structure and function of the genome, and potentially explain variations in genotype–phenotype relations (i.e., identical twins). "
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    ABSTRACT: Early life environments interact with genotype to determine stable phenotypic outcomes. Here we examined the influence of a variant in the brain-derived neurotropic factor (BDNF) gene (Val66Met), which underlies synaptic plasticity throughout the central nervous system, on the degree to which antenatal maternal anxiety associated with neonatal DNA methylation. We also examined the association between neonatal DNA methylation and brain substructure volume, as a function of BDNF genotype. Infant, but not maternal, BDNF genotype dramatically influences the association of antenatal anxiety on the epigenome at birth as well as that between the epigenome and neonatal brain structure. There was a greater impact of antenatal maternal anxiety on the DNA methylation of infants with the methionine (Met)/Met compared to both Met/valine (Val) and Val/Val genotypes. There were significantly more cytosine-phosphate-guanine sites where methylation levels covaried with right amygdala volume among Met/Met compared with both Met/Val and Val/Val carriers. In contrast, more cytosine-phosphate-guanine sites covaried with left hippocampus volume in Val/Val infants compared with infants of the Met/Val or Met/Met genotype. Thus, antenatal Maternal Anxiety × BDNF Val66Met Polymorphism interactions at the level of the epigenome are reflected differently in the structure of the amygdala and the hippocampus. These findings suggest that BDNF genotype regulates the sensitivity of the methylome to early environment and that differential susceptibility to specific environmental conditions may be both tissue and function specific.
    Development and Psychopathology 02/2015; 27(1):137-50. DOI:10.1017/S0954579414001357 · 4.89 Impact Factor
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    • "Thompson and colleagues also noted that DNA methylation from saliva and whole blood were more similar to each other when compared to lymphoblastoid cell lines, presumably due to the effects of transformation and culture conditions [Thompson et al., 2013]. Despite the interest in peripheral tissues other than blood, few studies have utilized saliva samples for genome-wide DNA methylation surveys [Ghadirivasfi et al., 2011; Essex et al., 2013; Melas et al., 2013; Yang et al., 2013]. Saliva is readily collectable, but the proportion of buccal epithelial cells and leukocytes varies between individuals and results in substantial cellular heterogeneity. "
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    ABSTRACT: DNA methylation has become increasingly recognized in the etiology of psychiatric disorders. Because brain tissue is not accessible in living humans, epigenetic studies are most often conducted in blood. Saliva is often collected for genotyping studies but is rarely used to examine DNA methylation because the proportion of epithelial cells and leukocytes varies extensively between individuals. The goal of this study was to evaluate whether saliva DNA is informative for studies of psychiatric disorders. DNA methylation (HumanMethylation450 BeadChip) was assessed in saliva and blood samples from 64 adult African Americans. Analyses were conducted using linear regression adjusted for appropriate covariates, including estimated cellular proportions. DNA methylation from brain tissues (cerebellum, frontal cortex, entorhinal cortex, and superior temporal gyrus) was obtained from a publically available dataset. Saliva and blood methylation was clearly distinguishable though there was positive correlation overall. There was little correlation in CpG sites within relevant candidate genes. Correlated CpG sites were more likely to occur in areas of low CpG density (i.e., CpG shores and open seas). There was more variability in CpG sites from saliva than blood, which may reflect its heterogeneity. Finally, DNA methylation in saliva appeared more similar to patterns from each of the brain regions examined overall than methylation in blood. Thus, this study provides a framework for using DNA methylation from saliva and suggests that DNA methylation of saliva may offer distinct opportunities for epidemiological and longitudinal studies of psychiatric traits. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2015; 168(1). DOI:10.1002/ajmg.b.32278 · 3.42 Impact Factor
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    • "92,667 probes overlapping SNPs either at or within 10 bp of the targeted CpG site, and invariable probes with a mean beta-value ≥0.95 or ≤0.05 across case and control samples were removed from analysis [38], [39]. Sites were considered to be differentially methylated if they met the following selection criteria: the absolute beta-value difference between the mean beta-values of cases and controls was greater than 0.20, p≤0.05 according to the Wilcoxon rank-sum test, and FDR≤0.05 using the Benjamini-Hochberg procedure [40], following methods used in several previous epigenomic studies [29], [30], [33], [41], [42]. Lists of differentially methylated probes, regions, and their annotations were generated using sitetest, outputDMfunc, regionswrapper, and annotfunc IMA functions. "
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    ABSTRACT: Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months. Symptoms fail to dissipate after sufficient rest and have major effects on the daily functioning of CFS sufferers. CFS is a multi-system disease with a heterogeneous patient population showing a wide variety of functional disabilities and its biological basis remains poorly understood. Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored. We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences. Gene ontology (GO) and network analysis of differentially methylated genes was performed to determine potential biological pathways showing changes in DNA methylation in CFS. We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology.
    PLoS ONE 08/2014; 9(8):e104757. DOI:10.1371/journal.pone.0104757 · 3.23 Impact Factor
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