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）可能是一种系统性疾病，不仅影响大脑，而且影响 整个身体。根据每个机构，努力确定风险预测和诊断的生物学信号 已经在多个生物领域进行了，包括基因的 - 摩尼克评估 和表观遗传变化以及包括跨越多种生物标志物的组合的面板 系统。百万退伍军人计划（MVP）的大规模基因组协会研究 和精神病基因组学联盟（PGC）已鉴定出与PTSD相关的20个基因 诊断/症状和发达的多基因风险评分（PR），以预测发展的风险 暴露于创伤事件后的PTSD。增加PR，环境的表观遗传调解 影响可能是对PTSD敏感性差异的关键机制。最大的元 到目前 在军事人群中，确定了几个范围内的表观基因组明显的CPG和区分区域。 最后，一项旨在用于诊断Warzone-多运动生物标记鉴定的研究 相关的PTSD已经开发了一个多摩变诊断面板，该面板整合了蛋白质，代谢物， miRNA，甲基化和脊髓数据可预测PTSD诊断。虽然动力很好， 这些生物标志物是根据无偏见的方法开发的，这些生物标志物仍然是初步的 并等待特定患者人群的系统验证，例如寻求护理的退伍军人 对于VA的PTSD。如果PR，表观基因组签名和周围生物标志物面板不是 用PTSD复制在寻求治疗的退伍军人中，从 最终对退伍军人护理的临床公用事业的学术调查将不太可能。 VA 认识到这一需求并开发了RFA BX 21-043，该21-043旨在资助提案 “验证临床上显着的发现，例如识别治疗靶标或新颖的发现 基于从人群研究中获得的表型和“ OMIC”数据的生物标志物小组，… 包括遗传危险因素，病理生理途径，治疗目标识别和 生物标志物发现。”该提案的目的是验证PR，甲基化签名和 独立队列中的多摩尼克面板，从现有的纵向样本中收集了 寻求治疗的退伍军人。这些研究的结果将为开发提供高度信息 这些生物标志物用于精确医学应用。