Nemours Healthcare System for Children, Translational Health Disparities Science Research Program, Wilmington, DE 19803, USA.
Biological Sciences Department, University of Delaware, Newark, DE 19716, USA.
Int J Environ Res Public Health. 2019 Nov 4;16(21):4280. doi: 10.3390/ijerph16214280.
Early life stress (ELS) induced by psychological trauma, child maltreatment, maternal separation, and domestic violence predisposes to psycho-behavioral pathologies during adulthood, namely major depressive disorder (MDD), anxiety, and bipolar affective disorder. While environmental data are available in illustrating this association, data remain to be established on the epigenomic underpinning of the nexus between ELS and MDD predisposition. Specifically, despite the observed aberrant epigenomic modulation of the NR3C1, a glucocorticoid receptor gene, in early social adversity and social threats in animal and human models, reliable scientific data for intervention mapping in reducing social adversity and improving human health is required. We sought to synthesize the findings of studies evaluating (a) epigenomic modulations, mainly DNA methylation resulting in MDD following ELS, (b) epigenomic modifications associated with ELS, and (c) epigenomic alterations associated with MDD. A systematic review and quantitative evidence synthesis (QES) were utilized with the random effect meta-analytic procedure. The search strategy involved both the PubMed and hand search of relevant references. Of the 1534 studies identified through electronic search, 592 studies were screened, 11 met the eligibility criteria for inclusion in the QES, and 5 examined ELS and MDD; 4 studies assessed epigenomic modulation and ELS, while 2 studies examined epigenomic modulations and MDD. The dense DNA methylation of the 1F exon of the NR3C1, implying the hypermethylated region of the glucocorticoid receptor gene, was observed in the nexus between ELS and MDD, common effect size (CES) = 14.96, 95%CI, 10.06-19.85. With respect to epigenomic modulation associated with child ELS, hypermethylation was observed, CES = 23.2%, 95%CI, 8.00-38.48. In addition, marginal epigenomic alteration was indicated in MDD, where hypermethylation was associated with increased risk of MDD, CES = 2.12%, 95%CI, -0.63-4.86. Substantial evidence supports the implication of NR3C1 and environmental interaction, mainly DNA methylation, in the predisposition to MDD following ELS. This QES further supports aberrant epigenomic modulation identified in ELS as well as major depressive episodes involving dysfunctional glucocorticoid-mediated negative feedback as a result of allostatic overload. These findings recommend prospective investigation of social adversity and its predisposition to the MDD epidemic via aberrant epigenomic modulation. Such data will facilitate early intervention mapping in reducing MDD in the United States population.
早期生活压力（ELS）由心理创伤、儿童虐待、母婴分离和家庭暴力引起，会导致成年后患心理行为疾病，如重度抑郁症（MDD）、焦虑症和双相情感障碍。虽然环境数据可用于说明这种关联，但ELS 和 MDD 易感性之间的表观遗传基础仍有待确定。具体来说，尽管在动物和人类模型中观察到 NR3C1（糖皮质激素受体基因）的异常表观遗传调节，但仍需要可靠的科学数据来进行干预映射，以减少社会逆境并改善人类健康。我们试图综合评估以下方面的研究结果：（a）ELS 后 MDD 相关的表观遗传调节，主要是 DNA 甲基化；（b）与 ELS 相关的表观遗传修饰；（c）与 MDD 相关的表观遗传改变。使用随机效应荟萃分析程序进行了系统评价和定量证据综合（QES）。检索策略涉及 PubMed 和相关参考文献的手工搜索。通过电子搜索共确定了 1534 项研究，筛选了 592 项研究，11 项符合纳入 QES 的标准，其中 5 项研究评估了 ELS 和 MDD；4 项研究评估了表观遗传调节和 ELS，2 项研究评估了表观遗传调节和 MDD。NR3C1 的 1F 外显子的密集 DNA 甲基化，暗示糖皮质激素受体基因的高甲基化区域，在 ELS 和 MDD 之间存在关联，共同效应量（CES）=14.96，95%CI，10.06-19.85。关于与儿童 ELS 相关的表观遗传调节，观察到了高甲基化，CES=23.2%，95%CI，8.00-38.48。此外，MDD 显示出边缘性表观遗传改变，高甲基化与 MDD 风险增加相关，CES=2.12%，95%CI，-0.63-4.86。大量证据支持 NR3C1 和环境相互作用，主要是 DNA 甲基化，在 ELS 后 MDD 易感性中的作用。这项 QES 进一步支持了 ELS 中鉴定的异常表观遗传调节，以及涉及糖皮质激素介导的负反馈功能障碍的重度抑郁症发作，这是由于适应不良性负荷所致。这些发现建议通过异常的表观遗传调节来前瞻性地研究社会逆境及其对 MDD 流行的易感性。这些数据将有助于在美国人群中进行早期干预映射，以减少 MDD。
