Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mental Health Care Center, PTSD Clinical Research Program and Laboratory of Clinical Neuroendocrinology/Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA.
Am J Psychiatry. 2014 Aug;171(8):872-880. doi: 10.1176/appi.ajp.2014.13121571.
Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The authors examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene (NR3C1) in peripheral blood mononuclear cells and its relationship to glucocorticoid receptor sensitivity in Holocaust offspring.
Adult offspring with at least one Holocaust survivor parent (N=80) and demographically similar participants without parental Holocaust exposure or parental PTSD (N=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of GR-1F promoter methylation and of cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical clustering analysis was used to permit visualization of maternal compared with paternal PTSD effects on clinical variables and GR-1F promoter methylation.
A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1F promoter methylation.
This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.
在大屠杀幸存者的成年后代中，已经观察到母体和父体创伤后应激障碍（PTSD）的差异影响，表现在糖皮质激素受体敏感性和易患精神障碍方面。作者研究了母体和父体 PTSD 对糖皮质激素受体（GR-1F）基因（NR3C1）外显子 1F 启动子的外周血单个核细胞中 DNA 甲基化的相对影响，以及其与大屠杀后代中糖皮质激素受体敏感性的关系。
至少有一位大屠杀幸存者父母的成年后代（N=80）和在人口统计学上与无父母大屠杀暴露或父母 PTSD 相似的参与者（N=15）完成了临床访谈、自我报告测量和生物学程序。采集血液样本用于分析 GR-1F 启动子甲基化和低剂量地塞米松刺激后的皮质醇水平，采用母体和父体 PTSD 作为主要效应进行双因素方差分析。采用层次聚类分析允许可视化母体与父体 PTSD 对临床变量和 GR-1F 启动子甲基化的影响。
显著的交互作用表明，在没有母体 PTSD 的情况下，父体 PTSD 的后代表现出更高的 GR-1F 启动子甲基化，而同时具有母体和父体 PTSD 的后代表现出更低的甲基化。较低的 GR-1F 启动子甲基化与更大的地塞米松后皮质醇抑制显著相关。聚类分析显示，母体和父体 PTSD 的影响与临床指标和 GR-1F 启动子甲基化存在差异相关。
这是第一项研究表明，GR-1F 启动子甲基化与父母 PTSD 和神经内分泌结果有关。母体 PTSD 对父体 PTSD 效应的调节表明，创伤相关脆弱性的代际传递存在不同的机制。
