Genetic Architecture of Tinnitus and its Relationship to Hearing Loss

耳鸣的遗传结构及其与听力损失的关系

• 批准号: 10656407
• 负责人: Caroline M Nievergelt
• 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: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656407
• 关键词: Acoustic Trauma; Acoustics; Address; Age; Anatomy; Anxiety Disorders; Auditory; Biological; Biology; Brain; Chronic; Clinical; Cochlea; Cognition; Cognitive Therapy; Counseling; Data; Data Collection; Disease; Dissection; Ensure; Etiology; European ancestry; Exposure to; Foundations; Future; Genes; Genetic; Genetic Risk; Genomics; Goals; Health Care Visit; Hearing; Hearing Aids; Hearing Tests; Hearing problem; Heritability; Heterogeneity; Industrialization; Injury; Knowledge; Measures; Medial; Mental Depression; Meta-Analysis; Military Personnel; Modeling; Monitor; Neurobiology; Noise; Pathway interactions; Patient Self-Report; Pharmacologic Substance; Phenotype; Population Heterogeneity; Population Programs; Post-Traumatic Stress Disorders; Predisposition; Preparation; Productivity; Publishing; Quality of life; Research; Risk Factors; Secondary to; Signal Transduction; Sleep Deprivation; Speech Intelligibility; Subjective Tinnitus; Symptoms; Time; Tinnitus; Tissues; Traumatic Brain Injury; Twin Studies; United Kingdom; Untranslated RNA; Validation; Variant; Veterans; Vulnerable Populations; Work; age related; biobank; brain tissue; causal variant; clinical development; clinical diagnosis; clinical phenotype; clinically relevant; cohort; comorbidity; cost; disability; disability payment; effective therapy; gene discovery; genetic architecture; genetic variant; genome wide association study; genome-wide; hearing impairment; improved; indexing; military veteran; noise exposure; novel; patient population; phenomenological models; polygenic risk score; programs; protein protein interaction; risk prediction; risk variant; sleep difficulty; tool; trait; transcriptomics; vehicular accident

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.

自此以来，耳鸣和听力损失一直是退伍军人管理局排名第一和第二的残疾 2006 年，退伍军人管理局花费的超过数十亿美元的伤残补助金包括 医疗保健就诊、助听器费用和补救疗法，包括认知疗法 行为疗法。退伍军人的个人成本包括失去就业能力、失去 工作效率下降、生活质量下降以及睡眠困难和下降 认识。尚未确定有效治疗方法的原因之一可能是大 退伍军人群体在病因、暴露、遗传学、 和临床表型。 我们的小组发表了第一个大型全基因组关联研究（GWAS） 耳鸣），识别基因组变异并将耳鸣确立为可遗传的、多基因的 紊乱。我们收集了最大的耳鸣和听力相关数据 表型，包括具有广泛声学暴露范围的不同人群， 年龄、血统。我们现在希望继续这个高效的项目，以增加 基因发现并进一步剖析耳鸣和听力损失的基因组景观。 具体来说，听觉耳鸣的不同解剖学和基因组途径 损坏情况仍不明。 在目标 I 中，我们建议使用更多方法来扩展和完善耳鸣表型分析 比自我报告更严格的标准，即残疾评级和临床诊断。对于 在大型 GWAS 中，我们将首次使用基于 > 的客观听力测量 MVP 中的 350,000 个听力图，例如主成分和语音清晰度 指数（SII）。我们将描述暴露测量、相关的共病疾病 耳鸣、危险因素和多特征 GWAS 的协变量。目标 2 将使用我们的 建立了执行 GWAS 的管道，包括对 MVP 和 UKB 进行荟萃分析 在外部队列中复制。此外，我们将优化多元化的贡献 祖先来识别因果变异并确保我们对听觉的理解 遗传学延伸到 MVP 所代表的血统。我们将识别耳鸣 使用目标 1 中的多性状分析来确定亚型。在目标 3 中，我们将执行 GWAS 后的工作 功能分析，包括转录组插补关联 (TWAS) 来预测 相关大脑和耳蜗组织的转录组变异。在目标 4 中，我们将剖析 耳鸣、听力损失和丧失听力的共同和不同的遗传基础 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 评分（PRS）以更好地预测临床耳鸣风险。 成功完成这些目标将识别相关的变异、基因和 途径，增进我们对耳鸣遗传基础的了解，剖析其关系 听力损失，并将研究结果扩展到暴露于一系列听力损失的不同人群 环境声损伤。我们的研究结果将为未来奠定基础 神经生物学工作和指导未来的药物研究，旨在有效 治疗这种普遍性疾病。