High-Dimensional Mediation Analysis for Selecting DNA Methylation Loci Mediating Childhood Trauma and Cortisol Stress Reactivity
High-Dimensional Mediation Analysis for Selecting DNA Methylation Loci Mediating Childhood Trauma and Cortisol Stress Reactivity
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DOI：
10.1080/01621459.2022.2053136
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发表时间：
2022-03
影响因子：
3.7
通讯作者：
Xu Guo;Runze Li;Jingyuan Liu;Mudong Zeng
中科院分区：
文献类型：
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作者：
Xu Guo;Runze Li;Jingyuan Liu;Mudong Zeng
儿童期创伤往往通过DNA甲基化的介导作用影响皮质醇应激反应。Houtepen等人进行了一项研究，以调查DNA甲基化在皮质醇应激反应中的作用及其与儿童创伤的关系。该研究收集了85名健康个体的数据集，包括385，882个DNA甲基化位点、皮质醇应激反应性、儿童创伤问卷的一维评分以及几个协变量。科学上最感兴趣的是从385，882个基因座中识别出活跃的介导基因座。Houtepen等人进行了385，882个线性中介分析，每个分析中考虑一个位点，并确定了三个活跃的中介位点。最近，货车Kesteren和Oberski提出了一个坐标式中介过滤器（CMF），并将其应用于同一数据集。他们确定了五个活跃的介导位点。不幸的是，Houtepen等人鉴定的三个基因座与货车Kesteren和Oberski鉴定的五个基因座完全不同，这可能是因为Houtepen等人和货车Kesteren和Oberski在他们的分析中没有共同考虑所有基因座。高维度DNA甲基化位点确实需要新的技术来鉴定活性介导位点，并测试早期生活创伤应激对后来皮质醇改变的直接和间接影响。基于上述两个科学工作中相互矛盾的结果，我们开发了一个新的估计和测试程序，并将其应用于与这两个工作所分析的相同的数据集。我们确定了三个新的基因座：cg 19230917、cg 06422529和cg 03199124，其效应量和p值分别为321.196（p值= 0.035965）、418.173（p值= 0.000234）和471.865（p值= 0.001691）。这三个位点具有合理的神经生物学解释和统计学显着的影响，通过我们提出的测试。基于我们的新程序，我们进一步证实了童年创伤对皮质醇变化没有显著的直接影响-它只通过DNA甲基化间接影响皮质醇，并且间接影响是负面的。本文的补充材料可在网上查阅。
Abstract Childhood trauma tends to influence cortisol stress reactivity through the mediating effects of DNA methylation. Houtepen et al. conducted a study to investigate the role of DNA methylation in cortisol stress reactivity and its relationship with childhood trauma. The study collected a dataset consisting of 385,882 DNA methylation loci, cortisol stress reactivity, one-dimensional score on a childhood trauma questionnaire and several covariates for 85 healthy individuals. Of great scientific interest is to identify the active mediating loci out of the 385,882 ones. Houtepen et al. conducted 385,882 linear mediation analyses, in each of which one locus was considered, and identified three active mediating loci. More recently, van Kesteren and Oberski proposed a coordinate-wise mediation filter (CMF) and applied it to the same dataset. They identified five active mediating loci. Unfortunately, the three loci identified by Houtepen et al. are completely different from the five loci identified by van Kesteren and Oberski, probably because both Houtepen et al. and van Kesteren and Oberski did not consider all loci jointly in their analyses. The high dimensional DNA methylation loci indeed necessitate new techniques for identifying active mediating loci and testing the direct and indirect effects of the early life traumatic stress on later cortisol alteration. Motivated by the contradictory results in the aforementioned two scientific works, we develop a new estimating and testing procedure, and apply it to the same dataset as that analyzed by the two works. We identify three new loci: cg19230917, cg06422529 and cg03199124, and their effect sizes and p-values are 321.196 (p-value = 0.035965), 418.173 (p-value = 0.000234) and 471.865 (p-value = 0.001691), respectively. These three loci possess both reasonably neurobiological interpretations and statistically significant effects via our proposed tests. Based on our new procedure, we further confirm that the childhood trauma does not have significant direct effects on cortisol change—it only indirectly affects cortisol through DNA methylation, and the indirect effect is negative. Supplementary materials for this article are available online.