Childhood Trauma, DNA Methylation of Stress-Related Genes, and Depression: Findings From Two Monozygotic Twin Studies.
Childhood Trauma, DNA Methylation of Stress-Related Genes, and Depression: Findings From Two Monozygotic Twin Studies.
复制标题
DOI：
10.1097/psy.0000000000000604
复制
发表时间：
2018-09
影响因子：
3.3
通讯作者：
Zhao J
中科院分区：
文献类型：
--
作者：
Peng H;Zhu Y;Strachan E;Fowler E;Bacus T;Roy-Byrne P;Goldberg J;Vaccarino V;Zhao J
DNA 甲基化与早期生活压力和抑郁症有关。这项研究检查了五个与抑郁症状相关的压力相关基因中多个 CpG 探针的 DNA 甲基化的联合关联，并在两项同卵 (MZ) 双胞胎研究中测试了这些基因甲基化是否介导了童年创伤和抑郁之间的关联。当前的分析包括 119 对同卵双胞胎（84 对男性 [平均年龄 55 岁]，35 对女性 [平均年龄 36 岁]）。通过亚硫酸氢盐焦磷酸测序或 450K BeadChip 对 5 个应激相关基因（BDNF、NR3C1、SLC6A4、MAOA 和 MAOB）的外周血 DNA 甲基化进行定量。我们应用广义泊松线性混合模型来检查每个单个 CpG 甲基化与抑郁症状之间的关联。通过加权截断乘积法测试单个基因或所有五个应激相关基因中多个 CpG 作为通路的联合关联。进行中介分析来测试应激基因甲基化对童年创伤和抑郁症状之间关系的潜在中介作用。多个 CpG 探针显示出名义上的个体关联，但很少有能在多次测试中幸存下来。然而，在这两项研究中，基于基因或基因集的方法揭示了所有五个与压力相关的基因中 DNA 甲基化与抑郁症状的显着联合关联。此外，BDNF 和 NR3C1 中的两个 CpG 探针介导了约 20% 的童年创伤和抑郁症状之间的关联。多个 CpG 位点的 DNA 甲基化与抑郁症状共同相关，并且部分介导了童年创伤和抑郁之间的关联。我们的结果强调了测试多个 CpG 位点对复杂性状的综合影响的重要性，并可能揭示不良早期生活经历在生物学上嵌入的分子机制。
DNA methylation has been associated with both early life stress and depression. This study examined the combined association of DNA methylation at multiple CpG probes in five stress-related genes with depressive symptoms, and tested whether these genes methylation mediated the association between childhood trauma and depression in two monozygotic (MZ) twin studies. The current analysis comprised 119 MZ twin pairs (84 male pairs [mean 55 years], and 35 female pairs [mean 36 years]). Peripheral blood DNA methylation of five stress-related genes (BDNF, NR3C1, SLC6A4, MAOA, and MAOB) was quantified by bisulfite pyrosequencing or 450K BeadChip. We applied generalized Poisson linear mixed models to examine the association between each single CpG methylation and depressive symptoms. The joint associations of multiple CpGs in a single gene or all five stress-related genes as a pathway were tested by weighted truncated product method. Mediation analysis was conducted to test the potential mediating effect of stress gene methylation on the relationship between childhood trauma and depressive symptoms. Multiple CpG probes showed nominal individual associations, but very few survived multiple testing. Gene-based or gene-set approach, however, revealed significant joint associations of DNA methylation in all five stress-related genes with depressive symptoms in both studies. Moreover, two CpG probes in the BDNF and NR3C1 mediated ~20% of the association between childhood trauma and depressive symptoms. DNA methylation at multiple CpG sites are jointly associated with depressive symptoms, and partly mediates the association between childhood trauma and depression. Our results highlight the importance of testing the combined effects of multiple CpG loci on complex traits, and may unravel a molecular mechanism through which adverse early life experiences are biologically embedded.