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 paper, 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 sub-populations. Specifically, mediators in different sub-populations 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 sub-populations 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.

中文翻译：

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以非洲裔美国人为主的队列中表观基因组 PTSD 和创伤性应激的异质中介分析

DNA甲基化（DNAm）被认为通过介导创伤和PTSD之间的关系在创伤后应激障碍（PTSD）中发挥关键作用。然而，非洲裔美国人的创伤后应激障碍的这种潜在机制仍然未知。为了填补这一空白，在本文中，我们调查了 DNAm 如何在底特律社区健康研究 (DNHS) (2008-2013) 中调节创伤经历对 PTSD 症状的影响，该研究主要涉及非裔美国人成年人。为了实现这一目标，我们为高维潜在 DNAm 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是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，所提出的方法优于现有的同类和异构数据方法。我们还展示了来自 DNHS 研究的 125 名参与者和超过 450、000 个 CpG 站点的数据集的中介分析结果。所提出的方法找到了三个受试者亚组，并确定了与文献中与 PTSD 症状相关的基因（如 HSP90AA1 和 NFATC1）相对应的 DNAm 介质。我们的发现可能有助于未来对 PTSD 机制进行更细粒度的研究，以及开发新的 PTSD 治疗方法。