Validation of PTSD signals across multiple biological domains for the development of diagnostic biomarkers for PTSD in military populations to improve clinical care of Veterans

创伤后应激障碍（PTSD）可能是一种全身性疾病，不仅影响大脑， 整个身体。因此，识别用于风险预测和诊断的生物信号的努力 已经在多个生物学领域进行，包括基因的组学评估 和表观遗传变化，以及包括跨越多种生物标志物的组合的组 系统.百万退伍军人计划（MVP）的大规模全基因组关联研究 和精神病学基因组学联盟（PGC）已经确定了超过20个与PTSD相关的基因 诊断/症状和发展的多基因风险评分（PRS），以预测发展风险 创伤后应激障碍暴露于创伤性事件后。添加到PRS，环境的表观遗传介导 影响可能是PTSD易感性差异的关键机制。最大的Meta- 迄今为止使用战斗暴露前后血液衍生的甲基化变化进行的分析 在军事队列中鉴定了几个表观基因组范围内的显著CpG和分化区域。 最后，最近的一项研究，旨在多组学生物标志物鉴定诊断战区- 相关的创伤后应激障碍已经开发了一种多组学诊断面板，其整合了蛋白质，代谢物， miRNA、甲基化和激素数据预测PTSD诊断虽然动力很好， 这些PTSD的生物标志物是从无偏见的发现方法发展而来的，仍然是初步的 并等待在特定患者人群（如寻求护理的退伍军人）中进行系统验证 创伤后应激障碍如果PRS、表观基因组特征和外周生物标志物组不 在寻求治疗的PTSD退伍军人中复制，将这些推定的生物标志物从 对退伍军人护理的最终临床效用的学术研究将是不可能的。退伍军人管理局 认识到这一需要，并制定了RFA BX 21-043，旨在为以下建议提供资金： “验证临床上有意义的发现，如确定治疗靶点或新的 生物标志物面板基于从人群研究中获得的表型和“组学”数据，... 包括遗传风险因素、病理生理学途径、治疗靶点识别和 生物标志物的发现”该提案的目标是验证PRS、甲基化特征和 独立队列中的多组学小组，现有纵向样本收集自 寻求治疗的退伍军人这些研究的结果将为发展提供大量信息 这些生物标志物的精确医学应用。

Post-traumatic stress disorder (PTSD) is likely a systemic illness, affecting not only the brain, but the entire body. Accordingly, efforts to identify biological signals for risk prediction and diagnosis have been performed across multiple biological domains, including –omic assessments of genes and epigenetic changes, and panels including a combination of biomarkers spanning multiple systems. Large-scale genome-wide association studies by the Million Veteran Program (MVP) and Psychiatric Genomics Consortium (PGC) have identified >20 genes associated with PTSD diagnosis/symptoms and developed polygenic risk scores (PRS) to predict risk of developing PTSD after exposure to a traumatic event. Adding to PRS, epigenetic mediation of environmental influences may be a key mechanism of differential susceptibility to PTSD. The largest meta- analysis to date using blood-derived methylation changes prior to and following combat exposure in military cohorts identified several epigenome-wide significant CpGs and differentiated regions. Finally, a recent study aiming at multi-omic biomarker identification for diagnosing warzone- related PTSD has developed a multi-omic diagnostic panel which integrates protein, metabolite, miRNA, methylation and hormone data to predict PTSD diagnosis. Although well powered and developed from unbiased discovery approaches, these biomarkers for PTSD are still preliminary and await systematic validation across specific patient populations such as Veterans seeking care for PTSD at the VA. If the PRS, epigenomic signature, and peripheral biomarker panel are not replicated in treatment-seeking Veterans with PTSD, translating these putative biomarkers from academic investigations to eventual clinical utility for Veteran care will be unlikely. The VA recognizes this need and developed the RFA BX 21-043 which seeks to fund proposals to “validate clinically significant findings such as identification of a therapeutic target or novel biomarker panel based on phenotypic and “omic” data acquired from population studies, … including genetic risk factors, pathophysiological pathways, treatment target identification and biomarker discovery.” The goal of this proposal is to validate the PRS, methylation signature and multi-omic panel in independent cohorts with existing, longitudinal samples collected from treatment-seeking Veterans. Results of these studies will be highly informative for development of these biomarkers for precision medicine applications.