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）是伊拉克和阿富汗最近发生冲突的标志性障碍 自2000年以来，超过300,000名服务成员获得了首次MTBI诊断。尽管大多数MTBI 案例确实看到了正常运作的恢复 脑震荡后综合征（PC）可能导致长时间损害。对于这些人，康复 干预措施经常无效。识别可能会导致持续风险的生物学因素 可能预测康复结果的症状和/或因素将是增强的关键一步 MTBI的康复护理的个性化和优化。 越来越多的文献表明，PC症状的持久性可能与因素分开有关 从头部受伤本身，包括前/合并症的心理病理学。因此，与 MTBI后，心理病理学的脆弱性，例如遗传学，可能会议次优恢复的风险。 大规模全基因组关联研究（GWASS）的最新进展有助于遗传 多种疾病的脆弱性。在这些进步的基础上，我们可以使用GWAS结果来计算 多基因风险评分（PRSS），计算给定疾病或性状的个人累积遗传风险 通过总结整个基因组中的风险等位基因数量，并由每个等位基因的相对风险加权。叉- 使用PRS验证障碍（即使用一种疾病/性状的PR来预测另一种疾病的流行 同一人中的障碍/特征）已用于确定预测的遗传病因 相关条件。因此，从MTBI相关条件得出的PRS分数可能为更多的道路铺平道路 对基因如何中度MTBI恢复的强烈了解。 拟议的研究将收集有关退伍军人的全基因组数据，并具有来自两个来源的MTBI病史。 第一个将是通过明尼阿波利斯VA健康的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怪物康复中心。 第二个将是在两个大规模联盟工作中评估MTBI的退伍军人：精神病学基因组学 联盟-PTSD工作组（PGC-PTSD）和神经联盟（CENC）的慢性影响。 对于所有参与者，我们将从链接到九种疾病/特征的GWAS数据中得出PRS，理论上是 与MTBI结果有关。这些疾病/特征属于以下广泛类别：心理 （创伤后应激障碍，重度抑郁症，注意力缺陷 - 经历性障碍，交叉疾病 风险），神经系统（阿尔茨海默氏病，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将确定关联 在PRS和本地和财团样本中存在持续的PCS符号之间，并具有探索性 随访（AIM 1A）使用每个人的创伤事件病史作为多基因的环境压力源 基因逐环境相互作用分析。 AIM 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）。探索目标3将进行 一项全面的关联研究，使用从计算机记录中提取的多种表型数据 （包括诊断，健康因素和神经指数）。这种方法可用于识别合理 中间表型将阐明赋予遗传风险的机制。 拟议的项目将是查看与PC相关的遗传因素的最大项目，也是第一个 查看与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恢复的个性化遗传概况，这可以大大提高精度 MTBI后遗症康复护理的有效性。

项目成果

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。

• DOI: 10.1017/pen.2020.10
• 发表时间: 2020
• 期刊: Personality neuroscience
• 作者: Sun,Michael;Marquardt,CraigA;Disner,SethG;Burton,PhilipC;Davenport,NicholasD;Lissek,Shmuel;Sponheim,ScottR
• 通讯作者: Sponheim,ScottR

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

• DOI: 10.1089/neu.2021.0099
• 发表时间: 2022-04
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: Wilde EA;Wanner IB;Kenney K;Gill J;Stone JR;Disner S;Schnakers C;Meyer R;Prager EM;Haas M;Jeromin A
• 通讯作者: Jeromin A

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。

• DOI: 10.1080/13854046.2021.1998635
• 发表时间: 2023
• 期刊: The Clinical neuropsychologist
• 作者: Disner,SethG;Mattson,ElsaK;Nelson,NathanielW;Armistead-Jehle,Patrick
• 通讯作者: Armistead-Jehle,Patrick