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

慢性神经创伤对听力损失的基因组影响；

• 批准号: 10536525
• 负责人: Royce Ellen Clifford
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536525
• 关键词: Age; Age of Onset; Aging; Alzheimer' s Disease; Anatomy; Audiology; Auditory; Biological; Brain; Chronic; Clinical; Cochlea; Cognition; Cognitive Therapy; Combined Modality Therapy; Comprehension; Data; Data Reporting; Dementia; Diagnosis; Disease; Electronic Health Record; Ensure; Environment; Etiology; European ancestry; Financial compensation; Gender; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Transcription; Genetic study; Genomics; Genotype; Goals; Hearing; Hearing Aids; Hearing Tests; Heritability; Impaired cognition; Incidence; Individual; Knowledge; Measures; Medical Records; Mental Depression; Military Personnel; Modeling; Molecular; Nervous System Trauma; Neurocognitive; Neurologic; Noise; Participant; Pathway interactions; Patient Self-Report; Peripheral; Phenotype; Predictive Value; Psychometrics; Publishing; Questionnaires; Records; Recovery; Resolution; Risk; Risk Factors; Secondary to; Sensory Disorders; Signal Transduction; Speech; Speech Audiometry; Speech Intelligibility; Suicide; Testing; Time; Traumatic Brain Injury; Variant; Veterans; Work; age related; causal variant; clinical predictive model; cohort; comorbidity; dementia risk; disability; experience; gene discovery; genetic variant; genome wide association study; genomic data; hearing impairment; hearing loss phenotype; hearing loss treatment; indexing; innovation; middle age; mild cognitive impairment; mild traumatic brain injury; permanent hearing loss; polygenic risk score; predict clinical outcome; predictive modeling; programs; speech in noise; tool; trait

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.

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。这两种疾病合计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 即使是轻微的创伤性脑损伤，在噪音中理解言语也会使恢复变得复杂。此外，还有以下并发症 听力困难包括丧失就业能力、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，并且存在显着的遗传重叠 存在于阿尔茨海默病和听力损失之间。 我们理解中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，包含听力图和 TBI 数据，我们的首要目标是识别遗传 与有或没有 TBI 环境发生率的听力损失相关的变异。 TBI 的差异- 解剖学研究表明，由于衰老和噪音而引起的听力损失和听力困难 证明除了外周耳蜗损伤外，TBI 还存在中枢神经系统损伤。我们建议 使用客观听力数据进行首次大型基因组研究，使用了超过 120 万张听力图 373,744 名退伍军人参加了迄今为止最大规模的针对听力障碍特定病因的研究。 该研究将包括听力图阈值、言语心理测量以及言语清晰度测量 噪音来识别与 TBI 继发性听力困难相关的遗传变异、基因和通路。我们 然后将评估多基因风险评分 (PRS)，以预测那些最有可能患痴呆症的退伍军人 受益于早期联合治疗，例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多种表型的标准。我们已经汇总了 来自 VA 和 DoD 医疗记录的听力图数据，用于计算纯音平均值、主成分、 以及对预测语音清晰度指数的个体偏差的测量。然后我们将描述 TBI 的特征， 根据 MVP 问卷自我报告和诊断，轻度认知障碍和痴呆 电子健康记录。第二个目标是，我们将对不同血统的个体进行单独的 GWAS 在美国军队中使用多种表型，随后将 TBI 添加为 Gene x 环境 多变的。对识别的变体和基因的分析将包括功能注释，包括与 其他疾病和特征，对相关分子途径进行分类，并整合转录信息 从耳蜗和大脑将我们的结果集中到与听力障碍相关的基因上。探索性目标将 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）而设计。 该提案在多个方面具有创新性。我们聚集了全球最大的一批 在客观听力数据的最大集合中对患有 TBI 的受试者进行基因分型。这个数据 提供了足够显着的统计能力来检查 TBI 特异性听力损失的基因组学，主要 VA 的担忧。此外，这将是第一个大型 GWAS 来识别与目标相关的基因和变异。 听力图测量。成功实现这些目标将发现适合的变异、基因和途径 进一步开展治疗听力损失的生物学研究。最后，这项工作将为模型添加遗传成分 用于预测 TBI 后的临床结果，确定可从早期听力增强中受益的退伍军人 和认知疗法。