ABSTRACT

DNA methylation (DNAm) has been suggested to play a critical role in post-traumatic stress disorder (PTSD), through mediating the relationship between trauma and PTSD. However, this underlying mechanism of PTSD for African Americans still remains unknown. To fill this gap, in this article, we investigate how DNAm mediates the effects of traumatic experiences on PTSD symptoms in the Detroit Neighborhood Health Study (DNHS) (2008–2013) which involves primarily African Americans adults. To achieve this, we develop a new mediation analysis approach for high-dimensional potential DNAm mediators. A key novelty of our method is that we consider heterogeneity in mediation effects across subpopulations. Specifically, mediators in different subpopulations could have opposite effects on the outcome, and thus could be difficult to identify under a traditional homogeneous model framework. In contrast, the proposed method can estimate heterogeneous mediation effects and identifies subpopulations in which individuals share similar effects. Simulation studies demonstrate that the proposed method outperforms existing methods for both homogeneous and heterogeneous data. We also present our mediation analysis results of a dataset with 125 participants and more than $450,000$ CpG sites from the DNHS study. The proposed method finds three subgroups of subjects and identifies DNAm mediators corresponding to genes such as HSP90AA1 and NFATC1 which have been linked to PTSD symptoms in literature. Our finding could be useful in future finer-grained investigation of PTSD mechanism and in the development of new treatments for PTSD. Supplementary materials for this article are available online.

摘要

DNA 甲基化 (DNAm) 已被认为通过调节创伤与 PTSD 之间的关系，在创伤后应激障碍 (PTSD) 中发挥关键作用。然而，非洲裔美国人 PTSD 的这种潜在机制仍然未知。为了填补这一空白，在本文中，我们在底特律邻里健康研究 (DNHS)（2008-2013 年）中调查了 DNAm 如何介导创伤经历对 PTSD 症状的影响，该研究主要涉及非裔美国人成年人。为实现这一目标，我们为高维潜在 DNAm 中介体开发了一种新的中介分析方法。我们方法的一个关键新颖之处在于，我们考虑了跨亚群的中介效应的异质性。具体来说，不同亚群中的中介可能对结果产生相反的影响，因此在传统的同质模型框架下可能难以识别。相比之下，所提出的方法可以估计异质中介效应并识别个体具有相似效应的亚群。仿真研究表明，所提出的方法优于同类和异构数据的现有方法。我们还展示了一个包含 125 名及以上参与者的数据集的中介分析结果$450,000$来自 DNHS 研究的 CpG 位点。所提出的方法找到了三个受试者亚组，并确定了与HSP90AA1和NFATC1等基因相对应的 DNAm 介质，这些基因在文献中与 PTSD 症状有关。我们的发现可用于未来更细粒度的 PTSD 机制研究和 PTSD 新疗法的开发。本文的补充材料可在线获取。