DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse
DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse
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DOI：
10.1016/j.psychres.2018.04.064
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发表时间：
2018-07-01
影响因子：
11.3
通讯作者：
O'Keane, Veronica
中科院分区：
文献类型：
--
作者：
Farrell, Chloe;Doolin, Kelly;O'Keane, Veronica
抑郁症与下丘脑-垂体-肾上腺（HPA）轴活动的改变有关。解释这些改变的一个拟议机制是压力相关基因的 DNA 甲基化水平的变化，这是早年逆境 (ELA) 继发的。在 67 名个体（33 名抑郁症患者和 34 名对照者）中检查了文献中涉及的两个基因区域，即糖皮质激素受体基因 (NR3C1) 外显子 1F 和 FKBP5 基因内含子 7。我们研究了在 25 名抑郁症患者和 20 名对照者中评估的皮质醇浓度以及 ELA 测量值是否与这些候选基因区域的甲基化程度相关。抑郁症患者的 NR3C1 外显子 1F DNA 平均甲基化水平显着升高，并且发现甲基化程度与早晨皮质醇浓度呈正相关。 NR3C1 外显子 1F 内特定 CG 位点的 DNA 甲基化水平与儿童情感虐待的严重程度相关。 CG38 的 DNA 甲基化与抑郁症组的 HPA 轴和儿童情感虐待指标相关。没有发现 FKBP5 差异。我们的研究结果表明 NR3C1 外显子 1F 的高甲基化可能发生在抑郁症中。这种位点特异性表观遗传变化与较高的基础 HPA 轴活性相关，可能反映了获得性糖皮质激素受体抵抗。
Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance.