Gene networks specific for innate immunity define post-traumatic stress disorder.
Gene networks specific for innate immunity define post-traumatic stress disorder.
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特定于先天免疫的基因网络定义了创伤后应激障碍。
DOI：
10.1038/mp.2015.9
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发表时间：
2015-12
影响因子：
11
通讯作者：
Woelk CH
中科院分区：
文献类型：
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作者：
Breen MS;Maihofer AX;Glatt SJ;Tylee DS;Chandler SD;Tsuang MT;Risbrough VB;Baker DG;O'Connor DT;Nievergelt CM;Woelk CH
创伤后应激障碍（PTSD）的分子因素仍然知之甚少。以前研究PTSD机制的转录组学研究采用有针对性的方法在横截面框架下识别单个基因，缺乏对这些基因在系统水平上的行为和特性的整体看法。在这里，我们试图将基于无监督基因网络的方法应用于使用来自美国海军陆战队（N=188）的外周血白细胞的全转录组RNA-Seq基因表达的前瞻性实验设计，所述全转录组RNA-Seq基因表达在部署到冲突地区之前和之后获得。我们鉴定了共调节基因的离散组（即，共表达模块）并测试它们与PTSD的关联。我们在部署前和部署后都确定了一个模块，其中包含PTSD发展的假定因果特征，显示了先天免疫应答和干扰素信号传导（I型和II型）功能丰富的基因的过度表达。重要的是，这些结果在美国海军陆战队的第二个非重叠独立数据集（N=96）中得到了复制，进一步概述了先天免疫和干扰素信号传导基因在共表达模块中的作用，以解释PTSD发展的至少部分因果病理生理学。第二个模块，创伤暴露的后果，包含创伤后应激障碍的弹性签名和过度表达的基因参与止血和伤口反应，表明慢性水平的压力损害适当的伤口愈合期间/暴露于战场后，同时强调止血系统的作用，作为慢性应激的临床指标。这些发现为早期预防措施和先进的PTSD检测提供了新的见解，这可能会导致延迟或消除PTSD发展的干预措施。
The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.