Identification of Susceptibility Genes for Age-Related Hearing Loss

年龄相关性听力损失易感基因的鉴定

• 批准号: 9012793
• 负责人: BRAD SCHULTE
• 金额: $ 67.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9012793
• 关键词: Address; Age of Onset; Age-Years; Aging-Related Process; Algorithms; Alleles; Animal Model; Audiometry; Auditory; Biological; Biological Assay; Candidate Disease Gene; Case-Control Studies; Characteristics; Clinic; Clinical Research; Cochlea; Cognitive; Complex; Correlative Study; Coupled; DNA; DNA Sequence Alteration; Data; Databases; Development; Diagnostic tests; Disease; Ear; Elderly; Environmental Risk Factor; Etiology; European; Gene Expression; Genes; Genetic; Genetic Variation; Genetic study; Genome; Genotype; Hearing; Heritability; High Prevalence; Human; In Situ Hybridization; Inbred Mouse; Individual; Medical; Metabolic; Methods; Molecular Genetics; Nature; Noise; Pathway interactions; Pattern; Phenotype; Play; Predisposition; Presbycusis; Prevalence; Prevention; Procedures; Process; Public Health; Recording of previous events; Recruitment Activity; Relative Risks; Role; Sampling; Sensory; Severities; Specimen Handling; Stress; Susceptibility Gene; Temporal bone structure; Testing; Variant; age related; base; candidate marker; case control; cohort; common treatment; exome; exome sequencing; gene product; genetic risk factor; genetic variant; genome wide association study; genome-wide; hearing impairment; high risk; human morbidity; human subject; laser capture microdissection; longitudinal database; metabolic phenotype; mouse model; next generation sequencing; novel diagnostics; novel therapeutics; population based; prevent; proband; protein expression; repository; research study; screening; tool

Age-related hearing loss is a consequence of accumulated environmental stresses to the cochlea and an intrinsic genetically-controlled aging process, with as much as 60% of hearing losses in the elderly being attributable to heritability. The often uncertain medical and noise histories in human subjects coupled with the high variability in the age of onset, rate of progression and the nature and severity of the hearing impairments make it difficult to attribute presbyacusis to a specific cause. Moreover, this phenotypic variability and other characteristics strongly suggest that age-related hearing loss is a complex polygenic disorder possibly involving different alleles on multiple genes. Recent advances in next generation sequencing have provided a powerful new tool to address the genetic basis of many age-related diseases. Here we propose to investigate the genetic and molecular basis of human presbyacusis. This project takes advantage of our extensive and continuously growing database containing well documented medical, noise and auditory function histories along with DNA samples from large numbers of human subjects. It also capitalizes on the development of new algorithms based on audiograms and data from animal models to define specific age-related hearing loss phenotypes in our experimental subjects. Accordingly, we propose to perform a comprehensive population-based cohort molecular genetic study to provide information about genetic contributions to specific phenotypes and biological pathways involved with age-related hearing loss. Aim 3.1 recruits additional subjects to increase the size of our discovery and replication cohorts. Aim 3.2 identifies genetic variants associated with increased susceptibility to presbyacusis employing genome-wide association analysis using whole exome sequence data. Aim 3.3 determines the pathological and potential functional consequences of genetic variants causing age-related hearing loss by assessing the distribution and changes in the expression pattern of promising candidate gene products and their association with pathological changes in human temporal bones.

与年龄有关的听力损失是耳蜗累积环境压力的结果 以及内在的遗传控制衰老过程，老年人的听力损失占60％，这是由于遗传力。人类受试者中通常不确定的医学和噪声历史，以及发作时代的高度变异，进展率以及听力障碍的性质和严重程度，使得将长老会归因于特定原因变得困难。此外，这种表型变异性和其他特征强烈表明，与年龄相关的听力损失是一种复杂的多基因疾病，可能涉及多个基因上的不同等位基因。下一代测序的最新进展为解决许多与年龄有关疾病的遗传基础提供了强大的新工具。在这里，我们建议研究人类长老会的遗传和分子基础。该项目利用了我们广泛且不断增长的数据库，其中包含文献良好的医学，噪声和听觉功能历史记录以及来自大量人类受试者的DNA样本。它还基于听力图和来自动物模型的数据的新算法的发展，以定义我们实验性主题中与特定年龄相关的听力损失表型的开发。因此，我们建议进行一项全面的基于人群的队列分子遗传研究，以提供有关与年龄相关听力损失有关的特定表型和生物途径的遗传贡献的信息。 AIM 3.1招募其他主题，以增加我们的发现和复制队列的规模。 AIM 3.2使用整个外显子组序列数据，采用了全基因组关联分析来确定与长老会增加易感性相关的遗传变异。 AIM 3.3通过评估有希望的候选基因产物的分布和表达模式的变化及其与人类时间骨骼的病理变化的相关性，确定遗传变异的病理和潜在功能后果。