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

摘要 为了调查年龄相关性听力障碍 (ARHI) 和耳鸣的遗传基础，我们将进行分析 来自英国 500,000 名参与者的基因型阵列、全基因组估算和外显子组序列数据 生物样本库。我们将进行单一和罕见变异聚合关联测试：测试主效应、性别和 年龄特异性关联和相互作用（基因 x 基因；基因 x 环境；基因 x 年龄；基因 x 年龄；和 基因 x 性别）控制重要的混杂因素，例如噪音暴露。我们进行精细映射来逗弄 将功能性因果变异与连锁不平衡变异区分开来。我们还将测试多效性 并进行介导分析以确定是否已检测到生物或多效性。 此外，我们计划开发新方法来分析明确解释的估算遗传数据 关联分析期间基因型调用的不确定性。通过忽略或不正确地建模 由于估算基因型的不确定性，当前的方法检测关联的能力下降 以及假阳性结果率增加。因此，我们将开发分析估算数据的方法， 它正确地模拟了估算基因型数据的不确定性，以允许检测关联， 相互作用、多效性和精细映射。这些新方法将在以下国家进行彻底评估和实施： 我们的 SEQSpark 软件可对数百个数据进行数据质量控制、注释和关联分析 数千个带有估算基因型数据的样本。这项研究对公共卫生具有重大意义 通过向研究界提供有用的分析工具并进行强有力的、 全面调查 ARHI 和耳鸣的遗传病因学，这反过来将有助于风险预测， 预防、改进和新的治疗方式。

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.