Epigenomic mediation after adverse childhood experiences: a systematic review and meta-analysis

Figures & data

Figure 1. Flow diagram of study selection according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Table 1. Summary of DNA methylation changes associated with childhood adversity.

Gene	Direction of change	Notes	Quality score^a	References
NR3C1	Hyper-methylation	Differential methylation in central nervous tissues, but inconclusive in peripheral tissues	5.4/10	[15, 40, 42, 45, 46]
			6/13	[41]
FKBP5	Hypo-methylation (rs1360780 allele)	Increased severity of depressive symptoms; greater risk for adulthood PTSD	5/10	[42, 48]
			6/13	[10, 47]
SLC6A4	Hyper-methylation	Associated with major depressive disorder and childhood sexual and physical abuse	5/10	[50, 51]
			8/13	[49]
BDNF	Hyper-methylation	Global methylation related to total childhood trauma and physical abuse in samples with comorbid borderline personality disorder	5/10	[52, 53]
DRD2	Hyper-methylation	Childhood sexual abuse compounded with bulimia spectrum disorder	4/10	[54]
IL6	Hypo-methylation	Greater IL6 concentrations and reduced cortisol response	NA	[55]
MAOA	Hyper-methylation	Sexual abuse and depression was associated with hyper-methylation of MAOA first exon	5/13	[56]
OPRK1	Hypo-methylation	Decreased hydroxymethylation of intron 2 in the Kappa variant 1 region	5/10	[57]
OXTR	No change	Site-specific CpG methylation and child abuse predicted adulthood depression and anxiety	NA	[58]
SKA2	No change	SKA2 methylation levels and exposure to childhood abuse predicts risk of future PTSD	5/13	[59]
SSTR4	No change	Increased in subjects with ethanol dependence	6/10	[60]
MT-ND6	Hyper-methylation	Greater methylation and blunted cortisol response in subjects with ≥4 ACE categories	NA	[61]
rRNA	Hyper-methylation	Restricted to the hippocampus of suicide victims with a history of child abuse	6/10	[11]
LINE-1 sequence	Hypo-methylation	Lower methylation predicted by higher emotional abuse and general trauma scores	4/10	[62]
BAGE sequence	No change	Higher total trauma scores predicted BAGE methylation	4/10	[62]

^a Quality of evidence was determined using the Newcastle–Ottawa Scale (rating refers to number of stars out of 10 for case-control studies and out of 13 for cohort studies). PTSD: post-traumatic stress disorder; NA: scale not applicable; ACE: adverse childhood experience.

Figure 2. QQ-plot for epigenome-wide association study (EWAS) meta-analysis.

Figure 3. Induced Network Module Analysis for genes mapped to differentially methylated CpG sites (ConsensusPathDB).

Figure 4. Forest plot of candidate gene methylation variation (random-effects (RE) model using |r| correlation coefficients).

Figure 5. Funnel plot of studies included in candidate gene meta-analysis.

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