Exploring polygenic risk as a means for personalizing TBI rehabilitation

轻度创伤性脑损伤(MTBI)是最近伊拉克和阿富汗冲突的标志性障碍， 自2000年以来，超过300,000名服务人员首次接受mTBI诊断。尽管大多数mTBI 一些病例确实恢复了正常的功能，所谓的“悲惨的少数人”会出现持续的症状 脑震荡后综合征(PCS)，可导致长期损害。对于这些人来说，康复 干预措施往往是无效的。确定可能导致持续性疾病风险的生物因素 可能预测康复结果的症状和/或因素将是增强 重型颅脑损伤患者康复护理的个性化与最优化。 越来越多的文献表明，PCS症状的持续性可能与单独的因素有关 来自头部损伤本身，包括病前/共病的精神病理学。因此，与以下因素相关的因素 精神病理学的脆弱性，如遗传学，可能会带来mTBI后恢复不佳的风险。 大规模全基因组关联研究(GWASs)的最新进展有助于表征基因 一系列疾病的脆弱性。在这些进步的基础上，我们可以使用GWAS的结果来计算 多基因风险分数(PRSS)，它计算一个人在特定疾病或特征下的累积遗传风险 通过将整个基因组中的风险等位基因的数量相加，按每个等位基因的相对风险加权。克罗斯- 使用PR进行障碍验证(即使用来自一种障碍/特征的PR来预测另一种障碍/特征的患病率 同一人的疾病/特征)已被用来确定假定- 相关条件。因此，从mTBI相关情况得出的PRS评分可以为更多的 对基因如何调节mTBI恢复的深入理解。 这项拟议的研究将从两个来源收集具有mTBI病史的退伍军人的全基因组数据。 第一个将是通过明尼阿波利斯退伍军人健康中心转介接受mTBI治疗的1000名退伍军人的当地样本 护理系统(MVAHCS)物理医学和康复服务以及多发伤康复中心。 第二个将是退伍军人在两个大型财团的努力中进行的mTBI评估：精神病学基因组学 联合会-创伤后应激障碍工作组(PGC-PTSD)和神经创伤联合会(CENC)的慢性影响。 对于所有参与者，我们将从与9种障碍/特征相关联的Gwas数据中得出PRS，这些障碍/特征被理论上认为是 与mTBI结果相关。这些障碍/特征可分为以下几大类：心理障碍 创伤后应激障碍、重度抑郁障碍、注意缺陷多动障碍、交叉障碍 风险)、神经学(阿尔茨海默病、帕金森氏病)、认知(教育程度、童年 智力)和主观(主观幸福感)。拟议研究的目标1将确定两者之间的联系 在本地和联合体样本中存在持续性PCS症状与PRSS之间的关系，并进行了探索性研究 随访(目标1A)使用每个个体的创伤事件史作为多基因研究中的环境应激源 基因与环境的交互作用分析。AIM 2将使用PRSS来预测转诊退伍军人的治疗反应 用于mTBI相关症状的治疗(包括PCS或PTSD的治疗)。探索性目标3将进行 一项使用从计算机化记录中提取的各种表型数据的全表型关联研究 (包括诊断、健康因素和神经指标)。这种方法可以用来识别似是而非的 中间表型，这将阐明遗传风险被赋予的机制。 拟议中的项目将是研究与PCS相关的遗传因素的最大项目，也是第一个 看看与mTBI康复相关的遗传因素。这个项目的结果可以直接 可解释为用于mTBI恢复的个性化遗传简档，这可以显著提高精度 以及康复护理对脑外伤后遗症的疗效。

Mild traumatic brain injury (mTBI) is a signature disorder of recent conflicts in Iraq and Afghanistan, with over 300,000 service members receiving a first-time mTBI diagnosis since 2000. Though the majority of mTBI cases do see a return to normal functioning, a so-called “miserable minority” experience persistent symptoms of post-concussive syndrome (PCS) that can result in prolonged impairment. For these individuals, rehabilitative interventions are frequently ineffective. Identifying biological factors that might confer risk for persistent symptoms and/or factors that might predict rehabilitative outcomes would be a critical step towards enhancing the personalization and optimization of rehabilitative care for mTBI. A growing literature suggests that the persistence of PCS symptoms may be linked to factors separate from the head injury itself, including premorbid/comorbid psychopathology. As such, factors associated with vulnerability for psychopathology, such as genetics, likely confer risk for sub-optimal recovery following mTBI. Recent advances in large-scale genome-wide association studies (GWASs) have helped characterize genetic vulnerability for a wide range of disorders. Building off of these advances, we can use GWAS results to calculate polygenic risk scores (PRSs), which calculate an individual's cumulative genetic risk for a given disorder or trait by summing the number of risk alleles across the entire genome, weighted by each allele's relative risk. Cross- disorder validation using PRS (i.e. using PRS from one disorder/trait to predict the prevalence of another disorder/trait within the same person) has been used to identify shared genetic etiology between putatively- related conditions. Therefore, PRS scores derived from mTBI-related conditions could pave the way for a more robust understanding of how genes moderate mTBI recovery. The proposed study will collect genome-wide data on veterans with a history of mTBI from two sources. The first will be local sample of 1000 veterans referred for mTBI treatment through the Minneapolis VA Health Care System (MVAHCS) Physical Medicine and Rehabilitation service and Polytrauma Rehabilitation Center. The second will be veterans assessed for mTBI in two large-scale consortia efforts: the Psychiatric Genomics Consortium-PTSD Working Group (PGC-PTSD) and the Chronic Effects of Neurotrauma Consortium (CENC). For all participants, we will derive PRSs from GWAS data linked to nine disorders/traits that are theorized to be related to mTBI outcomes. These disorders/traits fall into the following broad categories: psychological (posttraumatic stress disorder, major depressive disorder, attention deficit-hyperactivity disorder, cross-disorder risk), neurological (Alzheimer's Disease, Parkinson's Disease), cognitive (educational attainment, childhood intelligence), and subjective (subjective well-being). Aim 1 of the proposed study will determine the association between PRSs and the presence of persistent PCS symptoms in local and consortia samples, with an exploratory follow-up (Aim 1A) using each individual's history of traumatic events as an environmental stressor in a polygenic gene-by-environment interaction analysis. Aim 2 will use PRSs to predict treatment response in veterans referred for treatment of mTBI-related symptoms (including management of PCS or PTSD). Exploratory aim 3 will conduct a phenome-wide association study using a wide variety of phenotypic data extracted from computerized records (including diagnoses, health factors, and neural indices). This approach can be used to identify plausible intermediate phenotypes, which would shed light on mechanisms by which genetic risk is conferred. The proposed project would be the largest to look at genetic factors associated with PCS and the first to look at genetic factors associated with mTBI rehabilitation. The results of this project could be directly interpretable as a personalized genetic profile for mTBI recovery, which could substantially improve the precision and effectiveness of rehabilitative care for mTBI sequelae.