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疾病， 自2000年以来，超过30万名服务人员接受了首次mTBI诊断。虽然大多数mTBI 虽然有些病例确实恢复了正常功能，但所谓的“悲惨的少数人”经历了持续的 脑震荡后综合征（PCS），可导致长期损害。对这些人来说， 干预措施往往无效。确定可能导致持续性高血压风险的生物因素 可能预测康复结果的症状和/或因素将是提高康复效果的关键一步。 mTBI康复护理的个性化和优化。 越来越多的文献表明，PCS症状的持续性可能与独立的因素有关。 包括病前/共病的精神病理学因此，与下列因素相关的因素 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）的最新进展有助于描述遗传学特征。 易受各种疾病的影响。在这些进步的基础上，我们可以使用GWAS的结果来计算 多基因风险评分（PRSs），计算个体对给定疾病或特征的累积遗传风险 通过将整个基因组中的风险等位基因的数量相加，并根据每个等位基因的相对风险进行加权。交叉- 使用PRS进行疾病验证（即使用一种疾病/特征的PRS预测另一种疾病/特征的患病率 同一个人内的疾病/特征）已被用于鉴定脓毒症之间共有的遗传病因学， 相关条件。因此，从mTBI相关疾病中得出的PRS评分可以为更多的 对基因如何调节mTBI恢复的深入了解。 这项拟议的研究将从两个来源收集有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诊接受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和多发性创伤康复中心。 第二个将是在两个大规模财团的努力中评估mTBI的退伍军人：精神病学基因组学 PTSD工作组（PGC-PTSD）和神经创伤慢性效应联盟（CENC）。 对于所有参与者，我们将从GWAS数据中推导出与九种疾病/特征相关的PRS，这些疾病/特征理论上被认为是 与mTBI结果有关。这些障碍/特征分为以下几大类： （创伤后应激障碍、重度抑郁症、注意力缺陷多动障碍、交叉障碍） 风险），神经（阿尔茨海默病，帕金森病），认知（教育程度，儿童 主观幸福感（Subjective Well-being）。拟议研究的目标1将确定 在本地和财团样本中，PRS与持续PCS症状的存在之间存在探索性差异， 随访（目标1A）使用每个人的创伤事件的历史作为一个多基因的环境应激源， 基因与环境交互作用分析目标2将使用PRS预测退伍军人的治疗反应 用于治疗mTBI相关症状（包括PCS或PTSD的管理）。探索性目标3将进行 使用从计算机记录中提取的各种表型数据进行的全表型关联研究 （包括诊断、健康因素和神经指标）。这种方法可以用来识别可能的 中间表型，这将阐明遗传风险的机制。 拟议的项目将是最大的研究与PCS相关的遗传因素，也是第一个 看看与mTBI康复相关的遗传因素。该项目的结果可以直接 可解释为用于mTBI恢复的个性化遗传图谱，这可以大大提高精确度 和mTBI后遗症康复护理的有效性。

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.