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Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach

Zhu, Yiwen; Lussier, Alexandre A; Smith, Andrew D A C; Simpkin, Andrew J; Suderman, Matthew J; Walton, Esther; Relton, Caroline L; Dunn, Erin C


Yiwen Zhu

Alexandre A Lussier

Andrew J Simpkin

Matthew J Suderman

Esther Walton

Caroline L Relton

Erin C Dunn


Background: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods.
Methods: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n=785). We first used principal components analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (ngenes=15), closing (ngenes=36), and expression (ngenes=8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported,
time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences.
Results: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction.
Conclusions: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept
for studying time-varying exposures and gene- or pathway-level epigenetic modifications.


Zhu, Y., Lussier, A. A., Smith, A. D. A. C., Simpkin, A. J., Suderman, M. J., Walton, E., …Dunn, E. C. (in press). Examining the epigenetic mechanisms of childhood adversity and sensitive periods: a gene set-based approach. Psychoneuroendocrinology, Article 105854.

Journal Article Type Article
Acceptance Date Jun 25, 2022
Online Publication Date Jun 27, 2022
Deposit Date Jun 30, 2022
Publicly Available Date Jun 28, 2023
Journal Psychoneuroendocrinology
Print ISSN 0306-4530
Publisher Elsevier
Peer Reviewed Peer Reviewed
Article Number 105854
Keywords childhood adversity, sensitive periods, ALSPAC, plasticity, epigenetics
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