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.

耳鸣和听力损失是弗吉尼亚州的第1和＃2残疾 2006年。VA的费用超过数十亿美元的残疾支付 医疗访问，助听器成本和补救疗法，包括认知 行为疗法。资深人士的个人成本涉及失业，丢失 工作中的生产力，生活质量降低以及睡眠困难并减少 认识。未确定有效治疗的原因之一可能是很大的 在病因，暴露，遗传学， 和临床表型。 我们的小组出版了首个全基因组关联研究（GWAS） 耳鸣），识别基因组变体并确定耳鸣为一种可遗传的多基因 紊乱。我们已经策划了耳鸣的最大数据集合和与听力有关的数据集合 表型，包括各种各样的人群，具有广泛的声学曝光， 年龄和祖先。我们现在希望继续这个高产的项目以增加 基因发现并进一步剖析耳鸣的基因组景观和听力损失。 具体而言，耳鸣的不同解剖学和基因组途径 损坏仍然不明。 在目的中，我建议使用更多 比自我报告的严格标准，即残疾评级和临床诊断。为了 第一次在大型GWAS中，我们将根据>> MVP中有35万张听力图，例如主要组件和语音清晰度 索引（SII）。我们将表征曝光措施，合并症相关的疾病 带有耳鸣，危险因素和多特征GWAS的协变量。 AIM 2将使用我们的 建立的管道以执行GWAS，包括对MVP和UKB的荟萃分析 外部队列中的复制。此外，我们将优化各种各样的贡献 识别因果变体并确保我们对听觉的理解 遗传学扩展到MVP中代表的祖先。我们将确定耳鸣 使用AIM 1的多特征分析的子类型。在AIM 3中，我们将执行GWAS后GWAS 功能分析包括转录组插补关联（TWA）以预测 相关大脑和人工耳蜗的转录组变异。在AIM 4中，我们将剖析 耳鸣的共享遗传基础，听力损失和丧失 语音清晰度以改善风险预测。我们将分析 带有其他疾病的听觉表型。此外，我们将评估多基因风险 分数（PR）可以更好地预测临床上耳鸣的风险。 这些目标的成功完成将确定相关的变体，基因和 途径，促进我们对耳鸣遗传基础的了解，剖析其关系 听力损失，并将发现扩展到暴露于一系列的不同人群 环境声学创伤。我们的发现将为未来提供基础 神经生物学工作和直接的未来药物研究，旨在有效 这种普遍疾病的治疗。