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，导致了长期的身体 以及对反应者，特别是PTSD和下呼吸道症状（LRS）的心理创伤， 十年后，有10-20％的症状应与PTSD诊断一致的症状。我们的 小组发现，WTC响应者中的PTSD与呼吸道疾病紧密相关，而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的病因有关。在我们对n = 195 WTC的发现队列的试点研究中 响应者，我们发现反应者与没有A的反应者之间的基因表达有显着差异 使用整个基因组转录组分析，当前WTC-PTSD诊断。相关基因中的表达 汇出的PTSD病例是当前病例和非案例之间的中介。重要的是，以前 与几个白介素（IL4，IL2）一起，与所暗示的基因（FKBP5，NR3C1）一起差异表达 与炎症性疾病有关的胰岛素受体，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复合材料 响应者并获得了.734的AUC。该复合材料还显示了与自我的牢固线性缔合 报道了PTSD症状严重程度，创伤后应激障碍清单（PCL）的量度（Spearman） r = 0.422）。这些初步发现支持基因表达研究的潜在重要性，以识别 PTSD的生物标志物。拟议的研究是基于这项令人兴奋的试点工作的 基因表达的变化随着PTSD症状严重程度的变化和LRS的变化，整个18个月。 我们将使用我们的银行血液样本进行最先进的高通量RNA测序（RNA-SEQ） 以平均测序深度为50m读取的全血的转录组曲线，每个样品读取 每个时间点（对于两个时间点中的每个时间点）。在本研究的目标1中，我们将调查协会 基因表达（基因，同工型和剪接变异水平）的变化与PTSD的变化之间 在基因的18个月期间的症状以及这些变化涉及的遗传途径；和 确定与PTSD症状变化相关的基因表达特征（GES）。在AIM 2中，我们将 评估GES是否与每个PTSD症状维度的变化有关（重新体验， 避免，麻木，高音）。我们期望找到调节的常见基因/途径 每个PTSD症状维度的变化。在AIM 3中，我们将测试潜在的方向性 GES评分与PTSD症状严重程度之间的关联，即GES是否在第一个时间点 18个月后预测PTSD严重程度，反之亦然。在AIM 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 PTSD症状严重程度的变化将介导 PTSD-LRS合并症。这将是第一项鉴定基因和同工型表达的纵向研究 与PTSD症状的变化相关的签名以及四个PTSD症状中的每一个 尺寸和合并LRS。对基于PTSD的生物学过程的深入了解， 通过确定维护PTSD的过程，可以识别其GES具有临床意义 针对干预措施，并将为WTC响应者以及其他的治疗开发提供信息 暴露于创伤的人群。