Xue Fei, Tang Xiwei, Kim Grace, Koenen Karestan C, Martin Chantel L, Galea Sandro, Wildman Derek, Uddin Monica, Qu Annie
Purdue University, West Lafayette, IN.
University of Virginia, Charlottesville, VA.
J Am Stat Assoc. 2022;117(540):1669-1683. doi: 10.1080/01621459.2022.2089572. Epub 2022 Jul 11.
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 and 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.
DNA甲基化（DNAm）被认为在创伤后应激障碍（PTSD）中起着关键作用，通过介导创伤与PTSD之间的关系。然而，非裔美国人PTSD的这种潜在机制仍然未知。为了填补这一空白，在本文中，我们在主要涉及非裔美国成年人的底特律邻里健康研究（DNHS，2008 - 2013年）中，研究DNAm如何介导创伤经历对PTSD症状的影响。为了实现这一点，我们开发了一种针对高维潜在DNAm中介变量的新的中介分析方法。我们方法的一个关键新颖之处在于，我们考虑了亚人群中介导效应的异质性。具体而言，不同亚人群中的中介变量可能对结果有相反的影响，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人群。模拟研究表明，所提出的方法在同质和异质数据方面均优于现有方法。我们还展示了来自DNHS研究的包含125名参与者和超过450,000个CpG位点的数据集的中介分析结果。所提出的方法发现了三个受试者亚组，并识别出与文献中与PTSD症状相关的基因（如 和 ）对应的DNAm中介变量。我们的发现可能有助于未来对PTSD机制进行更精细的研究以及开发PTSD的新治疗方法。
