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Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study
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Abstract
Background Exposure to early-life adversity is known to predict DNA methylation (DNAm) patterns that may be related to psychiatric risk. However, few studies have investigated whether adversity has time-dependent effects based on the age at exposure.Methods Using a two-stage structured life course modeling approach, we tested the hypothesis that there are sensitive periods when adversity induces greater DNAm changes. We tested this hypothesis in relation to two alternatives: an accumulation hypothesis, in which the effect of adversity increases with the number of occasions exposed, regardless of timing; and a recency model, in which the effect of adversity is stronger for more proximal events. Data came from the Accessible Resource for Integrated Epigenomic Studies, a subsample of mother-child pairs from the Avon Longitudinal Study of Parents and Children (n = 691-774).Results After covariate adjustment and multiple testing correction, we identified 38 CpG sites that were differentially methylated at 7 years of age following exposure to adversity. Most loci (n = 35) were predicted by the timing of adversity, namely exposures before 3 years of age. Neither the accumulation nor recency of the adversity explained considerable variability in DNAm. A standard epigenome-wide association study of lifetime exposure (vs. no exposure) failed to detect these associations.Conclusions The developmental timing of adversity explains more variability in DNAm than the accumulation or recency of exposure. Very early childhood appears to be a sensitive period when exposure to adversity predicts differential DNAm patterns. Classification of individuals as exposed versus unexposed to early-life adversity may dilute observed effects.
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“Early life is a special period characterized by a high level of plasticity and fast development (76).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [76]
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“recent clinical studies demonstrate that the developmental timing of childhood adversity, with sensitive periods before three years of age, explains more variability in DNA methylation than the accumulation or recency of exposure.39”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [39]
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“Epigenetics can regulate neuronal plasticity and memory consolidation.38–41”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [39]
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“Time since adversity can moderate the magnitude of epigenetic change,53 while repeated or varied sources of adversity may accumulate to produce larger epigenetic responses.54,55”
From The role of epigenetics in psychological resilience (2021) · cites this paper as [53]
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“It has been suggested that the timing of adversity explains more variability in DNA methylation than the accumulation or recency of exposure [216].”
From Food Addiction and Psychosocial Adversity: Biological Embedding, Contextual Factors, and Public Health Implications (2020) · cites this paper as [216]
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Conceptual and Methodological Issues in Studying Early Adversity and Development
Pollak, S. D., & Smith, K. E. (2026) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-061724-091000 · Cited by 1
The longitudinal effects of neglect on aggression and delinquency: Testing competing hypotheses
Lee, J. A., Logan‐Greene, P., Zhu, J., & Wilding, G. E. (2026) · Children and Youth Services Review · doi:10.1016/j.childyouth.2026.108832
Metadata
- Authors
- Dunn, E. C., Soare, T. W., Zhu, Y., Simpkin, A. J., Suderman, M. J., Klengel, T., Smith, A. D. A. C., Ressler, K. J., & Relton, C. L.
- Affiliations
- Broad Institute (US)
- Massachusetts General Hospital (US)
- University of Bristol (GB)
- Harvard University (US)
- University of the West of England (GB)
- Corresponding author
- Dunn, Erin C.
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 85
- Issue
- 10
- Pages
- 838-849
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC6552666
- OpenAlex
- W2950440677
- Cited by
- 315
- References
- 92
- Citations by year
- 2026: 25 · 2025: 35 · 2024: 36 · 2023: 41 · 2022: 36 · 2021: 39 · 2020: 80 · 2019: 20
- FWCI
- 14.48
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWE Research Repository (UWE Bristol) (acceptedVersion, cc-by-nc-nd)
- Explore Bristol Research (acceptedVersion, cc-by-nc-nd)
- UWE Research Repository (UWE Bristol) (submittedVersion, cc-by-nc-nd)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Bristol Research (University of Bristol) (submittedVersion, cc-by-nc-nd)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Medical Research Council
- National Center for Research Resources
- Biotechnology and Biological Sciences Research Council (BB/I025263/1, BBI025751/1, MC_UU_12013/2, MC_UU_12013/8)
- National Center for Advancing Translational Sciences
- Economic and Social Research Council
- Harvard University
- University of Bristol
- Harvard Catalyst
- Wellcome Trust (102215/2/13/2)
- National Institutes of Health (K01MH102403, R01MH113930, UL1 TR001102)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- childhood adversity, DNA methylation, sensitive period, early childhood, differentially methylated CpG sites, mother-child pairs, epigenome-wide association study, psychiatric risk
- MeSH terms
- Adverse Childhood Experiences, Epigenome, Child, Child, Preschool, Female, Humans, Infant, Longitudinal Studies, Male, Parent-Child Relations, Prospective Studies, Time Factors, CpG Islands, DNA Methylation, Epigenesis, Genetic
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