Exploring polygenic risk as a means for personalizing TBI rehabilitation

探索多基因风险作为个性化 TBI 康复的手段

• 批准号: 10669663
• 负责人: Seth Gordon Disner
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669663
• 关键词: Address; Affect; Afghanistan; Alleles; Alzheimer' s Disease; Attention deficit hyperactivity disorder; Biological Factors; Bipolar Disorder; Candidate Disease Gene; Caring; Categories; Childhood; Chronic; Clinic; Clinical; Cognitive; Communities; Complex; Craniocerebral Trauma; Data; Department of Defense; Development; Diagnosis; Disease; Education; Effectiveness; Environment; Etiology; European ancestry; Failure; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genome; Genotype; Health; Healthcare Systems; Impairment; Individual; Injury; Intelligence; Intervention; Iraq; Light; Link; Literature; Major Depressive Disorder; Mental disorders; Military Personnel; Minority; Multiple Trauma; Nervous System Trauma; Neurologic; Neurological status; Outcome; Outpatients; Parkinson Disease; Participant; Pattern; Personal Satisfaction; Persons; Phase; Phenotype; Physical Medicine; Physical Rehabilitation; Play; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Prediction of Response to Therapy; Prevalence; Psychopathology; Quality of life; Recommendation; Recording of previous events; Records; Recovery; Recovery of Function; Rehabilitation Centers; Rehabilitation Outcome; Rehabilitation therapy; Relative Risks; Research; Risk; Role; Sampling; Schizophrenia; Source; Sum; Symptoms; Syndrome; Testing; Time; Trauma; United States Dept. of Health and Human Services; Validation; Variant; Veterans; Work; active duty; combat veteran; comorbidity; computerized; disorder risk; environmental stressor; experience; falls; follow-up; gene environment interaction; genome wide association study; genome-wide; improved; indexing; innovation; mild traumatic brain injury; military veteran; neural; persistent symptom; personalized decision; personalized intervention; personalized predictions; phenome; phenotypic data; polygenic risk score; precision genetics; psychiatric genomics; psychologic; recruit; rehabilitation service; rehabilitative care; risk variant; service member; theories; trait; traumatic event; whole genome; working group

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.

轻度创伤性脑损伤 (mTBI) 是近期伊拉克和阿富汗冲突的标志性疾病， 自 2000 年以来，超过 300,000 名军人接受了首次 mTBI 诊断。尽管大多数 mTBI 病例确实恢复了正常功能，所谓的“悲惨少数”经历了持续的症状 脑震荡后综合症（PCS）可能会导致这些人的长期损伤。 识别可能带来持续风险的生物因素的干预措施常常无效。 可能预测康复结果的症状和/或因素将是加强康复的关键一步 mTBI 康复护理的个性化和优化。 越来越多的文献表明 PCS 症状的持续存在可能与不同的因素有关 头部损伤本身，包括病前/共病的精神病理学因素。 精神病理学的脆弱性，例如遗传学，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（GWAS）的最新进展有助于表征遗传特征 基于这些进展，我们可以使用 GWAS 结果来计算。 多基因风险评分 (PRS)，计算个体特定疾病或性状的累积遗传风险 通过对整个基因组中风险等位基因的数量求和，并按每个等位基因的相对风险进行加权。 使用 PRS 进行疾病验证（即使用一种疾病/性状的 PRS 来预测另一种疾病/性状的患病率） 同一个人的疾病/特征）已被用来识别假定的共同遗传病因—— 因此，从 mTBI 相关条件得出的 PRS 评分可以为更多的研究铺平道路。 对基因如何调节 mTBI 恢复的深入了解。 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。 第一个样本是通过明尼阿波利斯退伍军人管理局转介接受 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。 第二个将是在两个大型联盟项目中对退伍军人进行 mTBI 评估：精神病基因组学 联盟-PTSD 工作组 (PGC-PTSD) 和神经创伤慢性影响联盟 (CENC)。 对于所有参与者，我们将从与九种疾病/特征相关的 GWAS 数据中得出 PRS，这些疾病/特征理论上是 这些疾病/特征与 mTBI 结局相关。 （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）、神经系统（阿尔茨海默病、帕金森病）、认知（教育程度、童年 智力）和主观（主观幸福感）将确定该关联。 本地和联合样本中 PRS 与持续性 PCS 症状之间的关系，并进行了探索性研究 后续行动（目标 1A）使用每个人的创伤事件史作为多基因中的环境压力源 目标 2 将使用 PRS 来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）将进行探索性目标 3。 使用从计算机记录中提取的各种表型数据进行全表型关联研究 （包括诊断、健康因素和神经指数）。 中间表型，这将揭示遗传风险的机制。 拟议的项目将是研究与 PCS 相关的遗传因素的最大项目，也是第一个 研究与 mTBI 康复相关的遗传因素 该项目的结果可能是直接的。 可解释为 mTBI 恢复的个性化基因图谱，可大幅提高精确度 以及 mTBI 后遗症康复护理的有效性。

项目成果

A Framework to Advance Biomarker Development in the Diagnosis, Outcome Prediction, and Treatment of Traumatic Brain Injury.

促进创伤性脑损伤诊断、结果预测和治疗中生物标志物开发的框架。

• 发表时间: 2022-04
• 影响因子: 4.2
• 作者: Wilde, Elisabeth A;Wanner, Ina;Kenney, Kimbra;Gill, Jessica;Stone, James R;Disner, Seth;Schnakers, Caroline;Meyer, Retsina;Prager, Eric M;Haas, Magali;Jeromin, Andreas
• 通讯作者: Jeromin, Andreas

Posttraumatic stress symptomatology and abnormal neural responding during emotion regulation under cognitive demands: mediating effects of personality.

认知需求下情绪调节过程中的创伤后应激症状和异常神经反应：人格的中介作用。

• 发表时间: 2020
• 作者: Sun, Michael;Marquardt, Craig A;Disner, Seth G;Burton, Philip C;Davenport, Nicholas D;Lissek, Shmuel;Sponheim, Scott R
• 通讯作者: Sponheim, Scott R

The role of posttraumatic stress symptoms on memory complaints and performance in active-duty service members.

创伤后应激症状对现役军人记忆抱怨和表现的作用。

• 发表时间: 2023-01
• 作者: Disner, Seth G;Mattson, Elsa K;Nelson, Nathaniel W;Armistead
• 通讯作者: Armistead