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)可能是一种系统性疾病，不仅影响大脑，而且 整个身体。因此，为风险预测和诊断确定生物信号的努力 已经在多个生物领域进行了研究，包括对基因的基因组评估 和表观遗传变化，以及包括跨越多个 系统。百万退伍军人计划(MVP)进行的大规模全基因组关联研究 和精神病学基因组联盟(PGC)已经确定了20个与创伤后应激障碍相关的基因 诊断/症状和开发多基因风险评分(PR)以预测发生风险 暴露于创伤性事件后的创伤后应激障碍。添加到PR，环境的表观遗传调节 影响可能是创伤后应激障碍不同易感性的关键机制。最大的Meta- 迄今使用战斗暴露前后血源性甲基化变化的分析 在军事队列中，确定了几个表观基因组范围内显着的CPG和分化区域。 最后，最近一项旨在识别多个生物标志物以诊断战区的研究-- 相关的创伤后应激障碍已经开发出一种多组学诊断小组，它将蛋白质、代谢物、 MiRNA、甲基化和激素数据预测创伤后应激障碍的诊断。尽管动力充足， 从无偏见的发现方法发展而来，这些创伤后应激障碍的生物标记物仍然是初步的 并等待特定患者群体的系统验证，如寻求治疗的退伍军人 退伍军人事务部的创伤后应激障碍。如果PR、表观基因组签名和外周生物标记物小组没有 在患有创伤后应激障碍的寻求治疗的退伍军人中复制，将这些假定的生物标志物从 不太可能对退伍军人护理的最终临床效用进行学术调查。退伍军人事务部 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 “确认有临床意义的发现，如确定治疗靶点或新药 基于从人群研究中获得的表型和“基因组”数据的生物标志物小组，… 包括遗传风险因素、病理生理途径、治疗目标识别和 生物标记物的发现。该提案的目标是验证PRS、甲基化签名和 独立队列中的多组学小组，现有的纵向样本来自 寻求治疗的退伍军人。这些研究的结果将为发展提供高度的信息。 在这些生物标记物中，用于精确医学应用。

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.