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. 2016 Jun 7;6(6):e830.
doi: 10.1038/tp.2016.95.

Severe Psychosocial Deprivation in Early Childhood Is Associated With Increased DNA Methylation Across a Region Spanning the Transcription Start Site of CYP2E1

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Free PMC article

Severe Psychosocial Deprivation in Early Childhood Is Associated With Increased DNA Methylation Across a Region Spanning the Transcription Start Site of CYP2E1

R Kumsta et al. Transl Psychiatry. .
Free PMC article

Abstract

Exposure to adverse rearing environments including institutional deprivation and severe childhood abuse is associated with an increased risk for mental and physical health problems across the lifespan. Although the mechanisms mediating these effects are not known, recent work in rodent models suggests that epigenetic processes may be involved. We studied the impact of severe early-life adversity on epigenetic variation in a sample of adolescents adopted from the severely depriving orphanages of the Romanian communist era in the 1980s. We quantified buccal cell DNA methylation at ~400 000 sites across the genome in Romanian adoptees exposed to either extended (6-43 months; n=16) or limited duration (<6 months; n=17) of severe early-life deprivation, in addition to a matched sample of UK adoptees (n=16) not exposed to severe deprivation. Although no probe-wise differences remained significant after controlling for the number of probes tested, we identified an exposure-associated differentially methylated region (DMR) spanning nine sequential CpG sites in the promoter-regulatory region of the cytochrome P450 2E1 gene (CYP2E1) on chromosome 10 (corrected P=2.98 × 10(-5)). Elevated DNA methylation across this region was also associated with deprivation-related clinical markers of impaired social cognition. Our data suggest that environmental insults of sufficient biological impact during early development are associated with long-lasting epigenetic changes, potentially reflecting a biological mechanism linking the effects of early-life adversity to cognitive and neurobiological phenotypes.

Conflict of interest statement

EJS Sonuga-Barke obtained speaker fees, consultancy, research funding and conference support from Shire Pharma. He also received Speaker fees from Janssen Cilag and Consultancy from Neurotech solutions, Aarhus University, Copenhagen University and Berhanderling, Skolerne, Copenhagen, KU Leuven. He obtained Book royalties from OUP and Jessica Kingsley. He also received grants from MRC, ESRC, Wellcome Trust, Solent NHS Trust, European Union, Child Health Research Foundation New Zealand, NIHR, Nuffield Foundation, Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO) and MQ - Transforming Mental Health. The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Exposure to severe early-life deprivation is negatively associated with performance in sociocognitive tasks in the English and Romanian Adoptees study (ERA) subsample included in methylomic profiling. Prolonged exposure (⩾6 months) was significantly associated with lower scores for (a) intelligence quotient (IQ) at the age of 15 (P=0.004) (b) and the Theory of Mind at the age of 11 (P=3.07 × 10−4).
Figure 2
Figure 2
A differentially methylated region (DMR) spanning the transcription start site of CYP2E1 shows significantly increased DNA methylation levels in adoptees exposed to severe early-life adversity. A DMR on chromosome 10 spanning nine sequential 450K array probes (chr10:135340445-135341026) was identified by comb-p. DNA methylation across this region is significantly elevated (combined P=2.21 × 10−10; corrected Šidák P=2.98 × 10−5) in individuals exposed to severe long-term (⩾6 months) institutional deprivation compared with the low-exposure (<6 months) group and UK control group. Data for an extended region around this DMR are shown in Supplementary Figure 4.
Figure 3
Figure 3
Exposure-associated DNA methylation variation is associated with Theory of Mind test performance. (a) For the 100 top-ranked exposure-associated differentially methylated positions (DMPs; see Supplementary Table 4), effect sizes for association with exposure group correlated significantly with effect sizes for association with Theory of Mind at the age of 11 (r=−0.89, P=2.23 × 10−35). The top 10 exposure-associated DMPs (see Table 1) are highlighted in red. (b) The CYP2E1 DMR associated with exposure group is also significantly associated with the Theory of Mind (combined P=4.87 × 10−9, corrected Šidák P=8.79 × 10−5). Associations between DNA methylation and Theory of Mind are shown for the nine probes constituting the DMR, with the previously used coloring scheme (UK adoptees: red, short deprivation exposure group: blue, extended exposure group: green).

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