Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors

Abstract

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.

Keywords: DNA methylation; GR; PTSD; memory.

Figure 1.

Human NR3C1 gene and the CpG region analyzed by bisulfite pyrosequencing. The 5′ region of the NR3C1 gene contains multiple first exons, corresponding to multiple transcriptional start sites and multiple mRNA splice variants. The region analyzed by pyrosequencing is illustrated by enlarged box, below the exon 1F. Numbering is relative to the alternative transcription start site in exon 2. The CpG3 and CpG4 sites are encompassed by the potential NGFI-A binding site. Adapted from Oberlander et al. (2008).

Figure 2.

DNA methylation of NR3C1 promoter and PTSD symptoms in male genocide survivors. Association (Spearman's rank correlation, −log₁₀p) of DNA methylation marks across eight CpG positions in the human NR3C1 gene promoter with PTSD symptoms clusters intrusions, avoidance, and hyperarousal. The association between CpG3 and intrusions reached Bonferroni-corrected statistical significance (after correcting for 8 tests; P_Bonferroni = 0.008). The CpGs are aligned by genomic position. The position of the potential NGFI-A binding site is shaded in purple. The horizontal dashed line indicates the p < 0.05 Bonferroni-corrected significance threshold.

Figure 3.

Fitted values of probability for lifetime PTSD risk against DNA methylation at the NGFI-A binding site of the NR3C1 promoter for males and females. Lifetime PTSD risk was assessed against NR3C1 CpG3 DNA methylation and the number of lifetime traumatic event types via binary logistic regression (n_males = 83, p_{nominal_males} = 0.008, β_males = −0.519; n_females = 69, p_{nominal_females} = 0.243, β_females = −0.170). This graph also contains the raw CpG methylation values obtained in participants without (bottom line) and with (top line) PTSD.

Figure 4.

Methylation-dependent differences in brain activity related to successful recognition of previously seen pictures in healthy men. Displayed are voxels with a positive correlation between methylation values (at NR3C1_CpG3) and activity, using color-coded t values. The blue circles show the activation in the pars triangularis and pars orbitalis of the inferior frontal gyrus (centered at 44, 25, −4; peak p_{FWE corrected} < 0.05; displayed at p_uncorrected < 0.001; a random-effects, linear-regression model). Activations are overlaid on coronal (upper left), sagittal (upper right), and axial sections of the study-specific group template (see main text). L, Left side of the brain; R, right side of the brain.