Child abuse, depression, and methylation in genes involved with stress, neural plasticity, and brain circuitry
Open accessAbstract
Objectives To determine whether epigenetic markers predict dimensional ratings of depression in maltreated children.Method A genome-wide methylation study was completed using the Illumina 450K BeadChip array in 94 maltreated and 96 healthy nontraumatized children with saliva-derived DNA. The 450K BeadChip does not include any methylation sites in the exact location as sites in candidate genes previously examined in the literature, so a test for replication of prior research findings was not feasible.Results Methylation in 3 genes emerged as genome-wide-significant predictors of depression: DNA-Binding Protein Inhibitor ID-3 (ID3); Glutamate Receptor, Ionotropic N-methyl-D-aspartate (NMDA) 1 (GRIN1); and Tubulin Polymerization Promoting Protein (TPPP) (p < 5.0 × 10(-7), all analyses). These genes are all biologically relevant with ID3 involved in the stress response, GRIN1 involved in neural plasticity, and TPPP involved in neural circuitry development. Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5).Conclusions This study suggests that epigenetic changes in ID3, GRIN1, and TPPP genes, in combination with experiences of maltreatment, may confer risk for depression in children. The study adds to a growing body of literature supporting a role for epigenetic mechanisms in the pathophysiology of stress-related psychiatric disorders. Although epigenetic changes are frequently long lasting, they are not necessarily permanent. Consequently, interventions to reverse the negative biological and behavioral sequelae associated with child maltreatment are briefly discussed.
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Childhood maltreatment induces alterations in BDNF promoter methylation.
“Also, childhood maltreatment induces alterations in BDNF promoter methylation (75).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [75]
The Results (Epigenetic Predictors of Depression in Children) report methylation differences between maltreated and comparison children at BDNF sites, but explicitly state that all those sites are in the gene body, not the promoter. The study compares groups; it does not establish that maltreatment induces the differences. (LLM, conf=0.88)
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Experimental — accuracy not yet measuredA candidate gene study and an EWAS linked childhood adversity to increased methylation levels in GRIN2B/GRIND1 genes, suggesting evidence that this change may lead to the onset of depressive symptoms.
“Lastly, a candidate gene study (Engdahl, Alavian-Ghavanini, Forsell, Lavebratt, & Rüegg, 2021) and an EWAS (Weder et al., 2014) linked CA to increased methylation levels in GRIN2B/GRIND1 genes, suggesting evidence that this change may lead to the onset of depressive symptoms.”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Weder et al., 2014
The Results section (page unavailable) reports the opposite direction for GRIN1: greater methylation was associated with lower depression scores, not the onset of depressive symptoms. It reports methylation differences between maltreated and comparison children, but does not establish that childhood adversity increased GRIN1 methylation; the cited findings identify GRIN1, not GRIN2B or GRIND1. (LLM, conf=0.86)
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Experimental — accuracy not yet measuredNR3C1 methylation patterns are also altered in schizophrenia and BD, which may contribute to neuroendocrine dysfunction, although these findings are more variable.
“NR3C1 methylation patterns are also altered in schizophrenia and BD, which may contribute to neuroendocrine dysfunction in these disorders, although these findings are more variable”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [99]
The Results (page unavailable) report NR3C1 methylation differences between maltreated and comparison children, and correlations between methylation at two NR3C1 sites and morning cortisol. The paper does not report altered NR3C1 methylation or associated neuroendocrine dysfunction in schizophrenia or bipolar disorder; its findings concern a different population and condition. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAn EWAS in maltreated (n=94) vs. non-traumatized children (n=96) analyzing DNA methylation as a predictor of dimensional depression ratings discovered three significant CpG sites within ID3, GRIN1, and TPPP, with lower methylation correlating with increased depression scores.
“An EWAS in maltreated (n=94) vs. non-traumatized children (n=96) analyzing DNA methylation as a predictor of dimensional depression ratings discovered three significant CpG sites within the genes coding for the DNA-binding protein inhibitor ID-3 (ID3, chromosomal location 1p36.12), the inotropic glutamate receptor NMDA type subunit 1 (GRIN1, chromosomal location 9q34.3), and the tubulin”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Weder et al., 2014
All three CpG sites were predictors independent of interaction effects with childhood maltreatment.
“All three CpG sites were predictors independent of interaction effects with childhood maltreatment”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Weder et al., 2014
The ID3 CpG site showed an interaction effect with childhood maltreatment on cortisol secretion, with increased methylation predicting decreased diurnal cortisol secretion in controls, yet increased cortisol secretion in maltreated children.
“yet the ID3 CpG site showed an interaction effect with childhood maltreatment on cortisol secretion, with increased methylation predicting decreased diurnal cortisol secretion in controls, yet increased cortisol secretion in maltreated children (Weder et al., 2014).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Weder et al., 2014
Candidate genes studies have linked childhood adversity with DNAm changes in BDNF, consistently with EWAS data reporting DNAm changes affecting genes involved in neurogenesis.
“Candidate genes studies have linked CA with DNAm changes in BDNF (Moser et al., 2015; Thaler et al., 2014; Weder et al., 2014), consistently with EWAS data reporting DNAm changes affecting genes involved in neurogenesis (Prados et al., 2015; Uddin et al., 2010).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Weder et al., 2014
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References 64 · Cited by 324
Research works printed but not linked: 1
- [52]Orr CA Kaufman J Neuroscience and Child Maltreatment: The Role of Epigenetics in Risk and Resilience in Maltreated Children Society for Research in Child Development: Social Policy Report in press
- Authors
- Weder, N., Zhang, H., Jensen, K., Yang, B. Z., Simen, A., Jackowski, A., Lipschitz, D., Douglas-Palumberi, H., Ge, M., Perepletchikova, F., O'Loughlin, K., Hudziak, J. J., Gelernter, J., & Kaufman, J.
- Affiliations
- Child Mind Institute (US)
- Yale University (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Universidade Federal de São Paulo (BR)
- University of Vermont (US)
- Corresponding author
- Kaufman, Joan
- ORCID
- Venue
- Journal of the American Academy of Child & Adolescent Psychiatry
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 53
- Issue
- 4
- Pages
- 417-424.e5
- ISSN
- 0890-8567 (ISSN-L)
- PMC
- PMC4126411
- OpenAlex
- W2143923606
- Cited by
- 324
- References
- 64
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 15 · 2023: 16 · 2022: 29 · 2021: 47 · 2020: 30 · 2019: 29 · 2018: 40 · 2017: 36 · 2016: 25 · 2015: 22 · 2014: 10
- FWCI
- 36.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Academy of Child & Adolescent Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- National Institutes of Health (5t32mh067763-10)
- National Institute on Alcohol Abuse and Alcoholism (AA11330R01, AA017535, R01AA017535, R01AA011330)
- National Institute of Mental Health (MH077087, R01MH077087, K23 MH01789, R01MH098073, K23MH001789, T32MH-067763, R01MH065519, MH098073, MH65519)
- National Institute on Drug Abuse (DA-12849, DA 12690, K99/R00 DA022891, K01DA24758, K99DA022891, K01DA024758, DA022251, R01DA012690, R00DA022891, R03DA022251, R01DA012849)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Keywords
- child abuse, depression, DNA methylation, epigenetics, ID3, GRIN1, TPPP, stress response, neuroplasticity, brain circuits, brain-derived neurotrophic factor, NR3C1, FKBP5, CpG sites, saliva DNA, depression risk, stress-related psychiatric disorders, epigenetic interventions
- MeSH terms
- Adolescent, Child, Child Abuse, Child, Preschool, Depression, Female, Humans, Male, Neoplasm Proteins, Nerve Net, Nerve Tissue Proteins, Neuronal Plasticity, Stress, Psychological, Receptors, N-Methyl-D-Aspartate, DNA Methylation, Epigenesis, Genetic, Inhibitor of Differentiation Proteins, Genome-Wide Association Study
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