Genetic Architecture of Tinnitus and its Relationship to Hearing Loss

耳鸣和听力损失一直是退伍军人管理局的头号和第二号残疾 2006年。退伍军人管理局支付的超过数十亿美元的伤残抚恤金包括 卫生保健就诊、助听器的费用和包括认知治疗在内的补救治疗 行为疗法。退伍军人的个人成本包括失去就业能力，损失 工作效率降低，生活质量下降，以及睡眠困难和减少 认知力。尚未确定有效治疗方法的原因之一可能是 退伍军人群体在病原学、暴露、遗传学、 和临床表型。 我们小组发表了第一个大型全基因组关联研究(GWAS) 耳鸣)，识别基因组变异，确定耳鸣是一种可遗传的多基因 无序。我们收集了最大规模的耳鸣和听力相关数据 表型，包括具有广泛声暴露范围的不同人群， 年龄和血统。我们现在希望继续这一富有成效的项目，以增加 基因发现，并进一步剖析耳鸣和听力损失的基因组图景。 具体地说，耳鸣的不同解剖和基因组途径 损失仍未确定。 在目标一，我们建议扩大和改进耳鸣表型，使用更多 比自我报告更严格的标准，即残疾评级和临床诊断。对于 第一次在大型全球听力评估中，我们将使用基于&GT的客观听力测量方法； MVP中的350,000个听力图，如主成分和语言清晰度 指数(SII)。我们将描述暴露措施、相关的共病障碍 与耳鸣、危险因素和多性状GWA的协变量有关。Aim 2将使用我们的 建立了执行GWAS的渠道，包括对MVP和UKB进行荟萃分析 在外部队列中复制。此外，我们还将优化多元化的贡献 祖先识别因果变异并确保我们对听觉的理解 遗传学跨越了MVP中所代表的祖先。我们会确认耳鸣 亚型使用目标1的多性状分析。在目标3中，我们将执行后GWAS 功能分析，包括转录归因关联(TWAS)预测 相关脑组织和耳蜗组织的转录变异。在目标4中，我们将剖析 耳鸣、听力损失和耳聋的共同和不同的遗传基础 提高语音清晰度以提高风险预测。我们将分析基因的相关性 听觉表型与其他障碍。此外，我们还将评估多基因风险。 评分(PR)可以更好地预测临床上耳鸣的风险。 成功完成这些目标将确定相关的变异、基因和 途径，提高我们对耳鸣遗传基础的认识，剖析它的关系 听力损失，并将研究结果扩大到接触一系列 环境声学创伤。我们的发现将为未来的研究提供基础 神经生物学工作和指导未来以有效为目标的药物研究 这种广泛性疾病的治疗。

Tinnitus and hearing loss have been the #1 and #2 disabilities at the VA since 2006. Costs to the VA in excess of billions of dollars in disability payments include health care visits, cost of hearing aids, and remedial therapies, including cognitive behavioral therapy. Personal cost to the Veteran involves loss of employability, lost productivity at work, reduced quality of life, as well as sleep difficulties and diminished cognition. One reason that no effective treatment has been identified may be the large heterogeneity in the Veteran population with respect to etiology, exposures, genetics, and clinical phenotype. Our group published the first large genome-wide-association study (GWAS) for tinnitus), identifying genomic variants and establishing tinnitus as a heritable, polygenic disorder. We have curated the largest collection of data of tinnitus and hearing-related phenotypes, comprising diverse populations with a wide range of acoustic exposure, age, and ancestry. We now wish to continue this highly productive project to increase gene discovery and further dissect the genomic landscape of tinnitus and hearing loss. Specifically, the divergent anatomic and genomic pathways for tinnitus from hearing damage remains unidentified. In Aim I we propose to expand and refine phenotyping for tinnitus using more stringent criteria than self-report, i.e., disability ratings and clinical diagnoses. For the first time in a large GWAS, we will use objective measures of hearing based on > 350,000 audiograms in MVP such as principal components and a speech intelligibility index (SII). We will characterize exposure measures, comorbid disorders associated with tinnitus, risk factors, and covariates for multi-trait GWAS. Aim 2 will use our established pipeline to perform GWAS, including meta-analysis on MVP and UKB with replication in external cohorts. In addition, we will optimize the contribution of diverse ancestries to identify causal variants and ensure that our understanding of auditory genetics extends across ancestries represented in MVP. We will identify tinnitus subtypes using the multi-trait analysis from Aim 1. In Aim 3, we will perform post-GWAS functional analysis including transcriptomic imputation association (TWAS) to predict transcriptomic variation in relevant brain and cochlear tissues. In Aim 4, we will dissect the shared and distinct genetic underpinnings of tinnitus, hearing loss, and loss of speech intelligibility to improve risk prediction. We Will analyze genetic correlations of auditory phenotypes with other disorders. In addition, we will evaluate polygenic risk scores (PRS) to better predict risk of tinnitus clinically. Successful completion of these aims will identify relevant variants, genes, and pathways, advance our knowledge of the genetic basis of tinnitus, dissect its relationship to hearing loss, and expand findings to diverse populations exposed to a range of environmental acoustic trauma. Our findings will provide a foundation for future neurobiological work and direct future pharmaceutical research aiming at effective treatment for this pervasive disorder.