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Table 4 Early stress-induced epigenetic modifications of candidate genes in humans

From: Epigenetic alterations following early postnatal stress: a review on novel aetiological mechanisms of common psychiatric disorders

Candidate gene Objective Model/tissue type Early stress/assessment age Epigenetic and expression changes Interpretation References
rRNA promoter Determine the effect of childhood abuse on methylation status of the rRNA promoter Retrospective
CA + suicide vs no CA + no suicide
Mean age 35 yrs.
N = 30
↑ methylation rRNA promoter and 5′ regulatory region in CA
↑ methylation of 21 of 26 CpG sites in CA
↓ rRNA expression in hippocampus
Childhood abuse ↑ methylation of rRNA promoter in the hippocampus of suicide completers in adulthood [98]
GR promoter Determine the effect of childhood abuse on the methylation status of the GR promoter and GR mRNA exp Retrospective
Child abuse
Mean age 34.6 yrs.
N = 36 M
↑ methylation of CpGs in GR promoter
↓ GR mRNA exp
↓ GR 1F mRNA exp
Childhood abuse ↑ methylation of individual CpGs within the GR promoter and GR1F exon resulting in ↓ GR and GR 1F mRNA expression in adult hippocampus [19]
Determine the effect of early stress on methylation status of the GR promoter Retrospective
Peripheral blood WBCs
Early stressa
Assessed: mean age 27.4 yrs.
N = 99
↑ CpG1 methylation w ↓ parental care or loss
↑ CpG3 methylation w maltreatment or parental loss
↔ CpG2, 4, 5–13 methylation w childhood adversity
Early stress ↑ methylation of individual CpGs of the GR promoter in adulthood [71]
Determine the effect of childhood maltreatment and severity on NR3C1 promoter methylation Retrospective
Peripheral blood WBCs
Childhood maltreatmentb
Assessed: mean ages and sample size
BPD 30.76 yrs. N = 101
MDD 41.63 yrs. N = 99
MDD + PTSD 37.33 yrs.
N = 15
↑ CpG 2–8 methylation of the NR3C1 gene promoter in maltreated participants
↑ severity of maltreatment ↑ methylation status of NR3C1 except for CpG1 site
Childhood maltreatment was associated with ↑ methylation of the NR3C1 gene promoter in peripheral blood in adulthood.
Number and severity of maltreatment correlated positively with methylation status
NR3C1 locus (6.5 million base pairs) Determine the effect of CA on a 6.5 Mbp loci centred on NR3C1 Retrospective
CA + suicide vs no CA + no suicide
Assessed: adulthood
N = 24
281 DMRs were identified
↑ methylation in 126 DMRs in controls
↑methylation in 155 DMRs in abused
3 clusters of DMRs mapped within α-, β- and γ- protocadherin (PCDH) gene family
DMRs enriched more in α-PCDH in the abused brains
Early stress has a broader epigenomics imprint expanding to promoters of genes both upstream and downstream to the NR3C1 gene and includes the PCDH gene family implicated in synaptic plasticity [69]
5HTT or SLC6A4 Determine the effect of CA on SLC6A4 promoter methylation and mRNA expression Retrospective
Peripheral blood DNA
Childhood adversitya
Assessed: adulthood
N = 102 MDD with or without CA
↑average methylation in promoter of SLC6A4 with CpG7 showing higher methylation in CA to no CA
↑ methylation in CpG2 of SLC6A4 associated with physical abuse
Childhood adversities were significantly associated with higher SLC6A4 promoter methylation in people with current MDD [76]
Determine the effect of CA on the methylation status of SLC6A4 promoter Retrospective
Lymphoblast cell lines
Childhood maltreatment
Assessed: mean age: M 49 yrs.
F 47 yrs.
N = 192
↑ overall SLC6A4 promoter methylation in abused male and female
↑ methylation of CpG1 and CpG 3 of SLC6A4 in abused females compared to non-abused
↔ in individual CpG sites in males
Childhood abuse increased methylation of CpGs in the promoter of SLC6A4 in adults [74, 75]
  1. ↑ increased, ↓ decreased, ↔ no change, yrs. years, CA child abuse, DNA deoxyribonucleic acid, mRNA messenger ribonucleic acid, exp expression, rRNA ribosomal ribonucleic acid, GR glucocorticoid receptor, M male, F Female, WBC white blood cell, BPD borderline personality disorder, PTSD post-traumatic stress disorder, MDD major depressive disorder, DMRs differentially methylated regions, PCDH protocadherin, NR3C1 nuclear receptor subfamily 3, group C, member 1, SLC6A4 solute carrier family 6, member 4 (neurotransmitter transporter)
  2. aEarly stress included: low levels of parental care, parental loss and childhood maltreatment
  3. bSexual, physical and emotional abuse; BPD had higher childhood maltreatment; MDD had lower maltreatment