Analysis of DNA Methylation in Young People: Limited Evidence for an Association Between Victimization Stress and Epigenetic Variation in Blood

Abstract

Objective DNA methylation has been proposed as an epigenetic mechanism by which early-life experiences become “embedded” in the genome and alter transcriptional processes to compromise health. The authors sought to investigate whether early-life victimization stress is associated with genome-wide DNA methylation. Method The authors tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994–1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime). Results Epigenome-wide analyses of polyvictimization across childhood and adolescence revealed few significant associations with DNA methylation in peripheral blood at age 18, but these analyses were confounded by tobacco smoking and/or did not survive co-twin control tests. Secondary analyses of specific forms of victimization revealed sparse associations with DNA methylation that did not replicate across different operationalizations of the same putative victimization experience. Hypothesis-driven analyses of six candidate genes in the stress response (NR3C1, FKBP5, BDNF, AVP, CRHR1, SLC6A4) did not reveal predicted associations with DNA methylation in probes annotated to these genes. Conclusions Findings from this epidemiological analysis of the epigenetic effects of early-life stress do not support the hypothesis of robust changes in DNA methylation in victimized young people. We need to come to terms with the possibility that epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.

Sensitive periods for the effect of childhood adversity on DNA methylation: Results from a prospective, longitudinal study

“…These results are consistent with at least one human longitudinal study (16) and multiple animal studies (21,22,24,25) in emphasizing the existence of sensitive periods (19,20) particularly occurring shortly after birth -when epigenetic programming is maximally dynamic in response to parental care disruptions and other environmental inputs. The lack of detectable sensitive periods in one recent study (32) may be due to focusing only on adversities occurring at or after 5 years of age. Interestingly, neither the accumulation nor recency of the adversity explained considerable variability in DNAm.…”

Annual Research Review: Rethinking childhood trauma‐new research directions for measurement, study design and analytical strategies

“…For example, much research is based on small, selected groups of children, with the assumption that results from these samples will generalise to the population at large ( where do we sample?) (Danese et al, ; Marzi et al, ). Furthermore, much research is based on complex measures of childhood trauma, with the assumption that different dimensions, such as threat, deprivation or unpredictability, have little relevance to the mechanisms involved or outcomes ( what do we measure as trauma?)…”

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci

“…As substantially more of the PTSD cases reported smoking compared to controls, this suggested that we should control for smoking in the EWAS. A comparable approach was taken by Marzi and colleagues 50 . In their study of DNA methylation in relation to victimization stress in adolescents, they noted experiment-wide significant associations in 3 of the 4 AHRR CpGs associated with PTSD.…”