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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
Hippocampus
CA + suicide vs no CA + no suicide
Assessed
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
Hippocampus
Child abuse
Assessed
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
[70]
NR3C1 locus (6.5 million base pairs) Determine the effect of CA on a 6.5 Mbp loci centred on NR3C1 Retrospective
Hippocampus
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