Genomic effects of chronic neurotrauma on hearing loss; relationship between hearing loss, TBI, mild cognitive impairment, and dementia

在世界范围内，听力损失和创伤性脑损伤(TBI)是中年痴呆的两大危险因素。 生活。这两种疾病加在一起约占潜在可修改归因风险的11% 痴呆症的分数。包括听力损害和困难的慢性听觉感觉障碍 即使是轻微的脑外伤，理解噪声中的语音也会使恢复变得复杂。此外，两种疾病的并存 听力障碍包括丧失就业能力、抑郁、认知障碍和自杀。对.的使用 助听器与延缓老年性痴呆的发病有关，并与显著的基因重叠有关 存在于阿尔茨海默氏症和听力损失之间。 我们理解中的一个关键差距是与脑外伤相关的听力损失的遗传易感性。vbl.使用 全球最大的基因组数据集，包括听力图和脑损伤数据，我们的首要目标是识别基因 与听力损失相关的变异与环境中的脑损伤发生率有关。TBI的区别在于- 解剖学研究表明，衰老和噪音导致的听力损失和听力障碍 除外周耳蜗性损伤外，还表现为中枢神经损伤。我们建议 用客观的听力数据进行第一次大型基因组研究，使用超过120万张听力图 373,744名资深参与者，这是迄今为止对听力障碍特定病因的最大规模研究。 这项研究将包括听力阈值，言语心理测量学，以及语言清晰度的测量 噪声用于识别与脑外伤继发听力障碍相关的遗传变异、基因和通路。我们 然后将评估多基因风险评分(PR)以预测哪些退伍军人患痴呆症的风险最高 从早期综合治疗中受益，如听力增强和神经认知治疗。 第一个具体目标将建立听力损失的多种表型标准。我们已经聚合了 来自VA和国防部病历的听力图数据，以计算纯音平均值、主成分、 以及个体与预测的语音清晰度指数的偏差的量度。然后我们将描述TBI的特征， 根据MVP问卷和诊断的自我报告，轻度认知障碍和痴呆症 电子健康记录。在第二个目标中，我们将在不同祖先的个体中进行单独的GWA 在美国军方中使用多种表型，随后添加了TBI作为基因x环境 变量。对已确定的变异体和基因的分析将包括功能注释，包括与 其他疾病和特征，分类相关的分子途径，并纳入转录信息 将我们的结果集中在与听力障碍相关的基因上。探索性的目标将是 制定并测试颅脑损伤后听力损失的多基因风险评分。痴呆症的预测模型将是 通过将PRS添加到其他已知的危险因素中来设计，包括轻度认知障碍、年龄、性别和脑外伤。 这项提议在几个方面是创新的。我们已经积累了世界上最大的 在客观测听数据的最大聚合范围内对患有脑损伤的受试者进行基因分型。此数据 提供了足够显著的统计学力量来研究脑损伤特异性听力损失的基因组学， 退伍军人事务部的关切。此外，这将是第一个识别与OBJECT相关的基因和变种的大型GWAS 听力图测量。成功实现这些目标将发现变异、基因和遵循的途径 以进一步开展治疗听力损失的生物学研究。最后，这项工作将在模型中添加一个遗传成分 用于预测颅脑损伤后的临床结果，确定将从早期听力增强中受益的退伍军人 和认知疗法。

World-wide, hearing loss and traumatic brain injury (TBI) are the top two risk factors for dementia in mid- life. Together the two disorders account for approximately 11% of the potentially modifiable attributable risk fraction for dementia. Chronic auditory sensory disorders including hearing damage and difficulties understanding speech in noise complicate recovery even from mild TBI. In addition, comorbidities of hearing difficulties include loss of employability, depression, difficulties with cognition, and suicide. The use of hearing aids is associated with the delay of the onset of age-related dementia, and significant genetic overlap exists between Alzheimer’s disease and hearing loss. A critical gap in our understanding consists of genetic vulnerabilities to hearing loss related to TBI. Using the largest global genomic dataset with audiogram and TBI data, our overarching objective is to identify genetic variants associated with hearing loss with and without the environmental incidence of TBI. The difference in TBI- induced hearing loss and hearing difficulties secondary to aging and noise is indicated by anatomic studies that demonstrate a central neurologic component with TBI in addition to peripheral cochlear damage. We propose to perform the first large genomic studies with objective audiologic data, using over 1.2 million audiograms in 373,744 Veteran participants, in the largest study to date of a specific etiology for hearing impairment. The study will include audiogram thresholds, speech psychometrics, and a measure of speech intelligibility in noise to identify genetic variants, genes, and pathways associated with hearing difficulties secondary to TBI. We will then assess a polygenic risk score (PRS) to predict those Veterans most at risk for dementia who might benefit from early combined treatment, such as hearing augmentation and neurocognitive therapy. The first specific aim will establish criteria on multiple phenotypes for hearing loss. We have aggregated audiogram data from the VA and DoD medical record to calculate pure-tone averages, principal components, and a measure of individual deviation from a predicted speech intelligibility index. We will then characterize TBI, mild cognitive impairment, and dementia according to self-report on MVP questionnaires and diagnoses in the electronic health record. In the second aim, we will conduct separate GWAS in individuals of diverse ancestries represented in the US military using multiple phenotypes, subsequently adding TBI as a Gene x Environment variable. Analysis of variants and genes identified will consist of functional annotation, including correlations with other disorders and traits, categorizing relevant molecular pathways, and incorporating transcription information from the cochlea and brain to focus our results to genes relevant to hearing impairment. An exploratory aim will formulate and test a polygenic risk score for hearing loss following TBI. A predictive model for dementia will be devised by adding the PRS to other known risk factors, including mild cognitive loss, age, gender, and TBI. This proposal is innovative in several ways. We have amassed the largest worldwide cohort of genotyped subjects with TBI within the largest aggregation of objective audiometric data. This data provides sufficient significant statistical power to examine the genomics of TBI-specific hearing loss, of major concern to the VA. Further, it will be the first large GWAS to identify genes and variants related to objective audiogram measures. Successful attainment of these goals will uncover variants, genes and pathways amenable to further biological study for treatment of hearing loss. Finally, this work will add a genetic component to a model for predicting clinical outcome after TBI, identifying Veterans who would benefit from early hearing augmentation and cognitive therapy.