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