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）是中年痴呆症的两大危险因素。 生活这两种疾病加在一起约占潜在可改变归因风险的11% 痴呆症的分数。慢性听觉障碍，包括听力损伤和困难 在噪声中理解语音使即使从轻度TBI恢复也复杂化。此外， 听力障碍包括丧失就业能力、抑郁、认知困难和自杀。使用 助听器与年龄相关性痴呆的发病延迟有关，并且有显著的遗传重叠 存在于阿尔茨海默病和听力损失之间。 我们理解的一个关键差距是与TBI相关的听力损失的遗传脆弱性。使用 最大的全球基因组数据集听力图和TBI数据，我们的首要目标是确定遗传 与听力损失相关的变异，有和没有TBI的环境发病率。TBI的区别- 解剖学研究表明， 除了外周耳蜗损伤外，还表现出TBI的中枢神经系统成分。我们建议 使用客观听力学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名退伍军人参与了迄今为止最大规模的听力障碍特定病因研究。 这项研究将包括听力图阈值，言语心理测量学，以及语言清晰度的测量， 噪声来识别与继发于TBI的听力障碍相关的遗传变异、基因和途径。我们 然后将评估多基因风险评分（PRS），以预测那些最有可能患痴呆症的退伍军人， 从早期的联合治疗中受益，如听力增强和神经认知治疗。 第一个具体目标是建立听力损失的多种表型标准。我们聚集了 从VA和DoD医疗记录的听力图数据来计算纯音平均值，主成分， 以及与预测的语音清晰度指数的个体偏差的量度。然后我们将描述TBI， 根据MVP问卷和诊断的自我报告， 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GWAS 在美国军队中使用多种表型，随后将TBI添加为基因x环境 变量鉴定的变体和基因的分析将包括功能注释，包括与 其他疾病和性状，分类相关的分子途径，并纳入转录信息 从耳蜗和大脑中分离出来，将我们的研究结果集中在与听力障碍相关的基因上。一个探索性的目标将 制定并测试TBI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添加到其他已知的风险因素，包括轻度认知丧失，年龄，性别和TBI。 这一建议在几个方面具有创新性。我们聚集了全球最大的 在客观听力数据的最大集合中对TBI受试者进行基因分型。该数据 提供了足够的显著统计能力来检查TBI特异性听力损失的基因组学， 关注VA。此外，这将是第一个大型的GWAS，以确定基因和变异相关的目标， 听力图测量。这些目标的成功实现将揭示变异、基因和途径 以进一步研究治疗听力损失的生物学方法。最后，这项工作将在模型中添加遗传组件 用于预测TBI后的临床结果，识别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.