Longitudinal genome-wide transcriptome study of PTSD symptom change in WTC responders

WTC 应答者 PTSD 症状变化的纵向全基因组转录组研究

• 批准号: 9392696
• 负责人: Pei-Fen Kuan
• 金额: $ 49.67万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9392696
• 关键词: Longitudinal; genome; wide; transcriptome; study

ABSTRACT The 9/11 World Trade Center terrorist attack was a massive disaster, resulting in long-term physical and psychological trauma to the responders, in particular PTSD and lower respiratory symptoms (LRS), with 10-20% of responders experiencing symptoms consistent with the diagnosis of PTSD a decade later. Our group found that PTSD in WTC responders is closely linked to their respiratory diseases, and PTSD mediated the relationship between WTC exposures and LRS. Genetic vulnerability and gene-environment interactions have been implicated in the etiology of PTSD. In our pilot study of a discovery cohort of N=195 WTC responders, we found significant differences in gene expression between responders with versus without a current WTC-PTSD diagnosis, using whole genome transcriptome analysis. Expression of relevant genes in remitted PTSD cases was intermediary between current cases and non-cases. Importantly, previously implicated genes (FKBP5, NR3C1) were differentially expressed along with several interleukin (IL4, IL2), insulin receptor, B-cell, lymphocytes and PTEN signaling pathways that are linked to inflammatory diseases and to cancers. We tested the resulting expression composite in an independent replication sample of N=87 responders and achieved an AUC of .734. The composite also showed a robust linear association with a self- reported measure of PTSD symptom severity, the Posttraumatic Stress Disorder Checklist (PCL) (Spearman r=0.422). These preliminary findings support the potential importance of gene expression research to identify biomarkers of PTSD. The proposed study builds on this exciting pilot work by evaluating association between changes in gene expression with changes in PTSD symptom severity and LRS across an 18-month period. Using our banked blood samples, we will conduct state-of-the-art high-throughput RNA-sequencing (RNA-Seq) to generate transcriptome profiles from whole blood at an average sequencing depth of 50M reads per sample per time point (for each of the two time points). In Aim 1 of this study, we will investigate the association between changes in gene expression (gene, isoform and splice variant levels) and changes in PTSD symptoms across an 18-month period at gene as well the genetic pathways implicated by these changes; and identify the Gene Expression Signature (GES) associated with change in PTSD symptoms. In Aim 2, we will evaluate whether the GES is associated with change in each PTSD symptom dimension (re-experiencing, avoidance, numbing, hyperarousal). We expect to find both common and distinct genes/pathways regulating the change in each PTSD symptom dimension. In Aim 3, we will test the directionality of prospective associations between the GES score and PTSD symptom severity, i.e., whether the GES at the first time point predicts PTSD severity 18 months later, and vice versa. In Aim 4, we will evaluate whether the change in GES is associated with change in LRS. We hypothesize that any association observed between the GES and LRS will be mediated by change in PTSD symptom severity, indicating shared biological mechanisms underpinning PTSD-LRS comorbidity. This will be the first longitudinal study to identify the gene and isoform expression signatures associated with change in PTSD symptoms overall, as well as each of four PTSD symptom dimensions and comorbid LRS. An in-depth understanding of the biological processes underpinning PTSD, and identification of its GES carries clinical significance by identifying processes that maintain PTSD and can be targeted for intervention, and will inform treatment development for WTC responders as well as other trauma-exposed populations.

抽象的 9/11世界贸易中心恐怖袭击是一场巨大的灾难，造成了长期的物质损失 以及对响应者的心理创伤，特别是创伤后应激障碍（PTSD）和下呼吸道症状（LRS）， 10-20% 的响应者在十年后出现与 PTSD 诊断一致的症状。我们的 研究小组发现世贸中心响应者的 PTSD 与其呼吸系统疾病密切相关，并且 PTSD 介导 WTC 暴露与 LRS 之间的关系。遗传脆弱性和基因-环境相互作用 与 PTSD 的病因学有关。在我们对 N=195 WTC 发现队列的试点研究中 反应者中，我们发现有反应者与无反应者之间的基因表达存在显着差异 目前的 WTC-PTSD 诊断，使用全基因组转录组分析。相关基因的表达 缓解的 PTSD 病例介于当前病例和非病例之间。重要的是，之前 相关基因（FKBP5、NR3C1）与几种白介素（IL4、IL2）一起差异表达， 与炎症性疾病相关的胰岛素受体、B 细胞、淋巴细胞和 PTEN 信号通路 和癌症。我们在 N=87 的独立复制样本中测试了所得的表达组合 响应者，AUC 为 0.734。该复合材料还表现出与自相关性强的线性相关性。 报告的 PTSD 症状严重程度衡量标准，创伤后应激障碍检查表 (PCL)（Spearman r=0.422）。这些初步发现支持基因表达研究的潜在重要性，以确定 PTSD 的生物标志物。拟议的研究建立在这项令人兴奋的试点工作的基础上，通过评估之间的关联 18 个月内基因表达随 PTSD 症状严重程度和 LRS 的变化而变化。 使用我们储存的血液样本，我们将进行最先进的高通量 RNA 测序 (RNA-Seq) 以每个样本 50M 读取的平均测序深度从全血生成转录组图谱 每个时间点（对于两个时间点中的每一个）。在本研究的目标 1 中，我们将调查这种关联 基因表达（基因、亚型和剪接变异水平）的变化与 PTSD 的变化之间 18个月期间的基因症状以及这些变化所涉及的遗传途径；和 识别与 PTSD 症状变化相关的基因表达特征 (GES)。在目标 2 中，我们将 评估 GES 是否与每个 PTSD 症状维度的变化相关（重新经历、 回避、麻木、过度警觉）。我们期望找到共同和独特的基因/途径调节 每个 PTSD 症状维度的变化。在目标3中，我们将测试前瞻性的方向性 GES 评分与 PTSD 症状严重程度之间的关联，即第一时间点的 GES 是否 预测 18 个月后 PTSD 的严重程度，反之亦然。在目标 4 中，我们将评估 GES 的变化是否 与 LRS 的变化有关。我们假设 GES 和 LRS 之间观察到的任何关联 将由 PTSD 症状严重程度的变化介导，表明共同的生物学机制 PTSD-LRS 合并症。这将是第一个鉴定基因和亚型表达的纵向研究 与总体 PTSD 症状变化相关的特征，以及四种 PTSD 症状中的每一种症状 尺寸和共病 LRS。深入了解创伤后应激障碍 (PTSD) 的生物过程， 其 GES 的识别通过识别维持 PTSD 的过程而具有临床意义，并且可以 成为干预的目标，并将为世贸中心响应者以及其他人员的治疗开发提供信息 遭受创伤的人群。