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

总结 为了研究年龄相关性听力损伤（ARHI）和耳鸣的遗传基础，我们将分析 来自英国50万名参与者的基因型阵列、全基因组插补和外显子组序列数据 生物银行我们将进行单一和罕见变异的聚集关联检验：检验主效应、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;以及 基因x性别）控制重要的混杂因素，例如噪声暴露。我们执行精细映射， 将功能性致病变异体与处于连锁不平衡的变异体分开。我们还会检测多效性 并进行介导分析以确定是否检测到生物或介导的多效性。 此外，我们计划开发新的方法来分析插补的遗传数据，明确说明 关联分析中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，当前方法检测关联的能力下降， 以及增加的假阳性发现率。因此，我们将开发分析插补数据的方法， 其适当地对估算的基因型数据不确定性进行建模以允许检测关联， 相互作用、多效性和精细映射。新的方法将得到彻底的评估和实施， 我们的软件可以对数百个数据进行数据质量控制、注释和关联分析， 数以千计的具有插补基因型数据的样本。这项研究具有重大的公共卫生潜力 通过为研究界提供有用的分析工具，并通过开展一项动力充足的， 全面调查ARHI和耳鸣的遗传病因，这反过来将有助于风险预测， 预防，以及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.