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

跨多个生物领域验证 PTSD 信号，以开发军人群体中 PTSD 的诊断生物标志物，从而改善退伍军人的临床护理

• 批准号: 10617231
• 负责人: Victoria B Risbrough
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617231
• 关键词: Address; Affect; Biological; Biological Markers; Blood; Blood specimen; Brain; Caring; Classification; Clinic; Clinical; DNA; Data; Development; Diagnosis; Diagnostic; Epigenetic Process; Ethnic Population; Exposure to; Funding; Future; Gene Expression; Genes; Genetic; Genotype; Goals; Heart Rate; Hormones; Immune system; Investigation; Laboratories; Measures; Mediation; Mental Health; Meta-Analysis; Methods; Methylation; MicroRNAs; Military Personnel; Participant; Pathway interactions; Peripheral; Phenotype; Physiological; Pilot Projects; Plasma; Population; Population Heterogeneity; Population Study; Post-Traumatic Stress Disorders; Predisposition; Prognosis; Proteins; RNA; Resolution; Risk; Sampling; Selection for Treatments; Signal Transduction; Specificity; Stress; Symptoms; System; Testing; Translating; Validation; Veterans; War; Whole Blood; biobank; biomarker development; biomarker discovery; biomarker identification; biomarker panel; blood-based biomarker; care seeking; clinical application; clinical care; clinically significant; cohort; combat; combat veteran; data integration; diagnostic biomarker; diagnostic panel; epigenome; epigenomics; genetic risk factor; genome wide association study; genome wide methylation; genome-wide; improved; military veteran; multi-ethnic; multiple omics; novel marker; patient population; polygenic risk score; precision medicine; prognostic; programs; psychiatric genomics; response; risk prediction; targeted biomarker; therapeutic target; trauma exposure; traumatic event

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.

创伤后应激障碍（PTSD）可能是一种全身性疾病，不仅影响大脑，还影响大脑。 整个身体。因此，努力识别生物信号以进行风险预测和诊断 已在多个生物领域进行，包括基因组学评估 和表观遗传变化，以及包括跨越多个生物标志物组合的面板 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 和精神病基因组学联盟 (PGC) 已鉴定出超过 20 个与 PTSD 相关的基因 诊断/症状并制定多基因风险评分（PRS）来预测罹患疾病的风险 经历创伤事件后的创伤后应激障碍（PTSD）。除了 PRS 之外，环境的表观遗传调节 影响可能是 PTSD 差异易感性的关键机制。最大的元 迄今为止使用战斗暴露之前和之后的血液甲基化变化进行的分析 在军事队列中确定了几个表观基因组范围内的重要 CpG 和差异区域。 最后，最近一项旨在诊断战区的多组学生物标志物识别的研究 相关的 PTSD 开发了一个多组学诊断面板，整合了蛋白质、代谢物、 miRNA、甲基化和激素数据可预测 PTSD 诊断。尽管动力充足且 这些 PTSD 生物标志物是通过公正的发现方法开发出来的，但仍处于初步阶段 并等待特定患者群体（例如寻求护理的退伍军人）的系统验证 VA 的 PTSD。如果 PRS、表观基因组特征和外周生物标志物组不符合 在寻求治疗的患有创伤后应激障碍 (PTSD) 的退伍军人中进行复制，将这些假定的生物标志物从 对退伍军人护理的最终临床效用进行学术调查的可能性不大。弗吉尼亚州 认识到这一需求并制定了 RFA BX 21-043，旨在资助以下提案： “验证具有临床意义的发现，例如治疗靶点或新颖的识别 基于从人群研究中获得的表型和“组学”数据的生物标记物组，…… 包括遗传风险因素、病理生理途径、治疗目标识别和 生物标志物的发现。”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 这些生物标志物用于精准医学应用。