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

基本信息

批准号：
10226902
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
项目类别：
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/10226902
关键词：
Address Adult Affect Age Age-Years Alzheimer&apos s Disease Bayesian Modeling Biological Clinical Code Communities Complex Computer software Data Data Set Detection Ensure 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 Lead 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 base biobank causal variant cognitive function comorbidity data quality design exome genetic architecture genetic risk factor genomic locus hearing impairment improved innovation insight large datasets novel novel strategies ototoxicity parallel processing peer pleiotropism rare variant recruit risk prediction screening sex simulation speech in noise statistics trait whole genome

项目摘要

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.

概括为了研究与年龄相关的听力障碍（ARHI）和耳鸣的遗传基础，我们将分析来自英国500,000参与者的基因型阵列，整个基因组和外部序列数据生物库。我们将进行单个和罕见的变体聚合关联测试：对主要影响，性别和年龄特定的关联和相互作用（基因X基因；基因X环境；基因X年龄；基因X年龄；基因x性别）控制重要的混杂因素，例如噪音曝光。我们执行精细的映射以取笑与链接不平衡的功能性因果变体不同。我们还将测试多效性并进行中介分析以确定是否已检测到生物学或介导的多效性。此外，我们计划开发新的方法来分析明确解释的估算的遗传数据在关联分析过程中，基因型调用的不确定性。通过忽略或不当建模估计基因型的不确定性，当前方法的检测能力降低了以及提高的假阳性发现率。因此，我们将开发分析估算数据的方法，适当地模拟了基因型数据不确定性，以允许检测关联，相互作用，多效性和精细映射。新方法将在我们的SEQSPARK软件可执行数百个数据质量控制，注释和关联分析数千个带有基因型数据的样本。这项研究有可能获得重要的公共卫生通过向研究社区提供有用的分析工具，并通过提供有用的分析工具来进行影响对Arhi和耳鸣的遗传病因的全面研究将有助于风险预测，预防，改善和新的治疗方式。