Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study

  • Erin C. Dunn
    Address correspondence to Erin C. Dunn, Sc.D., M.P.H., Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Simches Research Building 6th Floor, Boston, MA 02114.
    [email protected]
    Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

    Stanley Center for Psychiatric Research, The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Thomas W. Soare
    Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts

    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

    Stanley Center for Psychiatric Research, The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts
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  • Yiwen Zhu
    Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts
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  • Andrew J. Simpkin
    Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
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  • Matthew J. Suderman
    Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
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  • Torsten Klengel
    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

    Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts

    Department of Psychiatry and Psychotherapy, University Medical Center Gottingen, Germany
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  • Andrew D.A.C. Smith
    Applied Statistics Group, University of the West of England, Bristol, United Kingdom
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  • Kerry J. Ressler
    Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

    Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, Massachusetts
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  • Caroline L. Relton
    Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom

    Institute of Genetic Medicine, University of Newcastle, Newcastle upon Tyne, United Kingdom
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      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.


      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).


      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.


      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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      Linked Article

      • Do Sensitive Periods Exist for Exposure to Adversity?
        Biological PsychiatryVol. 85Issue 10
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          Early environmental experiences exert a profound influence on brain development, with lasting effects on emotion, cognition, and behavior throughout the lifespan. However, knowledge of how environmental experiences become embedded biologically to shape neurocognitive development in humans remains remarkably limited. In this issue of Biological Psychiatry, Dunn et al. (1) test several accounts of how adversity influences peripheral DNA methylation patterns from birth through middle childhood. This work is innovative in empirically evaluating different conceptual models of adversity effects with longitudinal data on multiple forms of adversity.
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      • Erratum
        Biological PsychiatryVol. 86Issue 1
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          Erratum to: “Sensitive Periods for the Effect of Childhood Adversity on DNA Methylation: Results From a Prospective, Longitudinal Study,” by Dunn et al. (Biol Psychiatry 2019; 85:838–849); 10.1016/j.biopsych.2018.12.023 .
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