Innovative approaches to elucidate the genetic etiology of age-related hearing impairment and tinnitus

阐明与年龄相关的听力障碍和耳鸣遗传病因的创新方法

• 批准号: 10685471
• 负责人: Paul L. Auer
• 金额: $ 52.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10685471
• 关键词: Address; Adult; Affect; Age; Age Years; Alzheimer' s Disease; Bayesian Modeling; Biological; Clinical; Code; Communication; Communities; Complex; Computer software; Data; Data Set; Detection; Environment; Environmental Risk Factor; Equation; Etiology; Family; Friends; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic study; Genotype; Health Personnel; Hearing; Impaired cognition; Individual; Intervention; Investigation; Labyrinth; Linear Regressions; Linkage Disequilibrium; Logistic Regressions; Logistics; Maps; Measurement; Measures; Mediating; Mediation; Methodology; Methods; Modality; Modeling; Noise; Obesity; Participant; Pathogenicity; Pharmaceutical Preparations; Phenotype; Population; Population Heterogeneity; Presbycusis; Prevention; Public Health; Quality Control; Research; Research Personnel; Risk Factors; Sampling; Smoking; Social isolation; Statistical Methods; Susceptibility Gene; Testing; Tinnitus; Trans-Omics for Precision Medicine; Uncertainty; Untranslated RNA; Variant; analytical tool; biobank; causal variant; cognitive function; comorbidity; data quality; design; exome; genetic architecture; genetic risk factor; genomic locus; hearing impairment; improved; innovation; insight; large datasets; noise exposure; novel; novel strategies; ototoxicity; parallel processing; peer; pleiotropism; rare variant; recruit; risk prediction; screening; sex; simulation; speech in noise; statistics; trait; whole genome

SUMMARY To investigate the genetic basis of age-related hearing impairment (ARHI) and tinnitus we will analyze genotype array, whole genome imputed and exome sequence data from 500,000 participants in the UK Biobank. We will conduct single and rare variant aggregate association tests: testing for main effects, sex and age specific associations and interactions (gene x gene; gene x environment; gene x age; gene x age; and gene x sex) controlling for important confounders, e.g. noise exposure. We perform fine mapping to tease apart functional causal variants from those which are in linkage disequilibrium. We will also test for pleiotropy and perform mediation analysis to determine if biological or mediated pleiotropy has been detected. Additionally, we plan to develop novel approaches to analyze imputed genetic data that explicitly account for the uncertainty in genotype calls during association analysis. By ignoring or improperly modeling the uncertainty in imputed genotypes, current methods suffer from a decreased ability to detect associations as well as an increased false positive findings rate. Therefore, we will develop methods to analyze imputed data, which properly models imputed genotype data uncertainty to allow for the detection of associations, interactions, pleiotropy and fine mapping. The novel methods will be thoroughly evaluated and implemented in our SEQSpark software to perform data quality control, annotation, and association analysis for hundreds of thousands of samples with imputed genotype data. This study has the potential for significant public health impact by providing a useful analytic tool to the research community and by conducting a well-powered, comprehensive investigation of the genetic etiology of ARHI and tinnitus which in turn will aid in risk prediction, prevention, and improved and new treatment modalities.

摘要 为了研究年龄相关性听力障碍(ARHI)和耳鸣的遗传基础，我们将分析 来自英国500,000名参与者的基因阵列、全基因组推算和外显子组序列数据 生物库。我们将进行单一和罕见的变量聚合关联测试：主效应、性别和 年龄相关和相互作用(基因x基因；基因x环境；基因x年龄；基因x年龄；以及 基因x性别)控制重要的混杂因素，例如噪音暴露。我们执行精细映射以调侃 将功能因果变异与那些处于连锁不平衡的变异分开。我们还将测试多效性 并执行中介分析以确定是否检测到生物多效性或中介多效性。 此外，我们计划开发新的方法来分析推测的基因数据，这些数据明确地解释了 关联分析中的基因不确定度。通过忽略或不正确地对 在归因于基因类型的不确定性，目前的方法受累于检测关联的能力降低，因为 以及更高的假阳性发现率。因此，我们将开发分析输入数据的方法， 其适当地对归因于的基因数据不确定性进行建模以允许检测关联， 相互作用、多向性和精细映射。这些新方法将在#年进行彻底评估和实施。 我们的SEQSpark软件可对数百个数据进行质量控制、注释和关联分析 数以千计的样本与推定的基因数据。这项研究有可能对公共卫生产生重大影响 通过向研究界提供有用的分析工具，并通过进行强大的、 对ARHI和耳鸣的遗传病因进行全面调查，这反过来将有助于风险预测， 预防、改进和新的治疗模式。

项目成果

Comparison of multiple imputation and other methods for the analysis of imputed genotypes.

• DOI: 10.1186/s12864-023-09415-0
• 发表时间: 2023-06-06
• 期刊: BMC genomics
• 影响因子: 4.4

The genetic contribution of the X chromosome in age-related hearing loss.

• DOI: 10.3389/fgene.2023.1106328
• 发表时间: 2023
• 期刊: FRONTIERS IN GENETICS
• 影响因子: 3.7
• 作者: Naderi, Elnaz;Cornejo-Sanchez, Diana M. M.;Li, Guangyou;Schrauwen, Isabelle;Wang, Gao T. T.;Dewan, Andrew T. T.;Leal, Suzanne M. M.
• 通讯作者: Leal, Suzanne M. M.