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

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

doi:10.1016/j.psyneuen.2022.105854

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

Psychoneuroendocrinology. 2022 Oct:144:105854. doi: 10.1016/j.psyneuen.2022.105854. Epub 2022 Jun 27.

Authors

Yiwen Zhu¹, Alexandre A Lussier², Andrew D A C Smith³, Andrew J Simpkin⁴, Matthew J Suderman⁵, Esther Walton⁶, Caroline L Relton⁷, Erin C Dunn⁸

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States. Electronic address: yiwenzhu@mail.harvard.edu.
² Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, United States.
³ Mathematics and Statistics Research Group, University of the West of England, Bristol, UK.
⁴ School of Mathematics, Statistics and Applied Mathematics, National University of Ireland, Galway, Ireland.
⁵ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁶ Department of Psychology, University of Bath, Bath, UK.
⁷ MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States; Department of Psychiatry, Harvard Medical School, Boston, MA, United States; Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, United States; Harvard Center on the Developing Child, Cambridge, MA, United States. Electronic address: edunn2@mgh.harvard.edu.

Abstract

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 component 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 (n_genes = 15), closing (n_genes = 36), and expression (n_genes = 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.

Keywords: ALSPAC; Childhood adversity; Epigenetics; Plasticity; Sensitive periods.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adverse Childhood Experiences*
Child
DNA Methylation / genetics
Epigenesis, Genetic / genetics
Humans
Longitudinal Studies

Abstract

Publication types

MeSH terms

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