Genetic Architecture of Tinnitus and its Relationship to Hearing Loss

耳鸣和听力损失一直是#1和#2残疾在VA，因为 2006.退伍军人事务部在残疾支付方面的费用超过数十亿美元，包括 健康护理访问，助听器的费用和补救治疗，包括认知 行为疗法退伍军人的个人成本包括失去就业能力， 工作效率，生活质量下降，以及睡眠困难和减少 认知.尚未确定有效治疗的一个原因可能是 退伍军人人群在病因学、暴露、遗传学 和临床表型。 我们的团队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，并建立耳鸣作为一种遗传性，多基因 disorder.我们已经策划了最大的耳鸣和听力相关的数据收集 表型，包括具有广泛声学暴露的不同人群， 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 基因发现和进一步剖析耳鸣和听力损失的基因组景观。 具体来说，不同的解剖学和基因组途径耳鸣从听力 损坏情况仍未查明。 在目的我，我们建议扩大和完善耳鸣表型使用更多 比自我报告更严格的标准，即，残疾评级和临床诊断。为 在大型GWAS中，我们将首次使用基于> MVP中的350，000个听力图，例如主成分和语音清晰度 索引（SII）。我们将描述暴露措施，共病疾病相关 耳鸣、危险因素和协变量的多性状GWAS。目标2将使用我们的 建立了执行GWAS的管道，包括MVP和UKB的荟萃分析， 在外部队列中复制。此外，我们还将优化各种 祖先来识别因果变异，并确保我们对听觉的理解 遗传学跨越MVP中所代表的祖先。我们将识别耳鸣 使用Aim 1中的多性状分析进行亚型分析。在目标3中，我们将执行GWAS后 功能分析，包括转录组插补关联（TWAS），以预测 相关脑和耳蜗组织中的转录组变异。在目标4中，我们将剖析 耳鸣、听力损失和听力损失的共同和独特的遗传基础 语音清晰度，以提高风险预测。我们将分析遗传相关性， 听觉表型与其他疾病。此外，我们将评估多基因风险 耳鸣的危害有哪些？ 成功完成这些目标将确定相关的变异，基因， 耳鸣的病因有哪些？耳鸣的病因有哪些？ 听力损失，并扩大调查结果，以不同的人群暴露于一系列的 环境声损伤我们的发现将为未来的研究奠定基础。 神经生物学工作和指导未来的药物研究，旨在有效地 治疗这种普遍性疾病。

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.