Functional Analysis of GWAS loci associated with hearing loss.

与听力损失相关的 GWAS 位点的功能分析。

• 批准号: 10593682
• 负责人: Gaurav K Varshney
• 金额: $ 25.58万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10593682
• 关键词: Acoustics; Adult; Affect; Age; Alleles; Animal Model; Behavior; Biological Models; CDH23 gene; CRISPR/Cas technology; Candidate Disease Gene; Complex; Data; Development; Diagnosis; Dimensions; Disease; Disease model; Drug Screening; Dyes; Embryonic Development; Ensure; Fertilization; Gene Silencing; Generations; Genes; Genetic; Goals; Hair Cells; Health; Hearing; Hearing Aids; Human; In Situ Hybridization; Infection; Injury; International; Investments; Knock-out; Label; Labyrinth; Larva; Libraries; Maps; Mechanoreceptors; Mediating; Messenger RNA; Methods; Molecular; Monitor; Morphology; Mutagenesis; Mutation; Noise; Orthologous Gene; Participant; Pathogenesis; Pathology; Patient Self-Report; Pattern; Persons; Pharmaceutical Preparations; Phenotype; Population; Presbycusis; Quality of life; Rehabilitation therapy; Reporter; Reporter Genes; Resources; Role; Startle Reaction; Swimming; System; Technology; Testing; Tissues; Transgenic Organisms; Variant; Visualization; Zebrafish; behavioral phenotyping; candidate identification; causal variant; cost; disease phenotype; exome sequencing; gene function; genome wide association study; genome-wide analysis; genomic locus; hearing impairment; hearing loss phenotype; inner ear development; insight; knockout gene; lateral line; loss of function; mRNA Expression; model organism; mutant; neuromast; neurosensory; next generation sequencing; novel; novel therapeutics; ototoxicity; paralogous gene; screening; spatiotemporal; therapeutic development

Hearing loss is a highly prevalent and debilitating neurosensory disorder associated with substantially reduced quality of life and overall health. It currently affects 430 million people worldwide; by 2050 this is expected to increase to nearly 2.5 billion and result 1 in 10 people requiring rehabilitation. About 50% of cases are predicted to have a genetic basis, however hearing loss can also be caused by other factors such as age, ototoxic drugs, noise, infection or injury. Low-cost next generation sequencing technologies have facilitated many genome-wide association studies (GWAS) and exome sequencing projects that have identified hundreds of variants and genes associated with hearing loss. There are currently more than 150 loci and over 100 genes associated with non- syndromic hearing loss, however few candidate genes have been identified for complex phenotypes such as age-related hearing loss (ARHL) or presbycusis, which is becoming increasingly common as the population ages. A GWAS conducted to identify candidate genes associated with ARHL identified 44 independent genomic loci associated with hearing loss. A nearest gene was mapped for each SNP identified in this study, yet how this SNP influences gene function in hearing loss has not been determined. Establishing a linkage between the target genes and the disease phenotype is a huge challenge that ultimately affects the correct diagnosis; generating similar phenotypes upon gene inactivation in animal models can establish a strong support for a candidate gene. We identified 39 orthologs of 44 GWAS candidate genes in zebrafish, and further selected 29 novel genes that will be tested functionally for their role in hearing loss by (1) generating a library of zebrafish mutants for 29 (and paralogs) candidate genes associated with ARHL (2) analyzing these mutants via a high-throughput phenotyping pipeline including morphological, cellular, and behavioral phenotypes. Identifying the functional consequences of the candidate genes in zebrafish will yield mechanistic insights in disease pathogenesis.

听力损失是一种非常普遍和衰弱的感觉神经障碍， 生活质量和整体健康。它目前影响着全世界4.3亿人;到2050年， 增加到近25亿，导致十分之一的人需要康复。大约50%的病例预测 然而，听力损失也可能由其他因素引起，如年龄，耳毒性药物， 噪音、感染或损伤。低成本的下一代测序技术已经促进了许多全基因组测序。 关联研究（GWAS）和外显子组测序项目，已经确定了数百个变异和基因 与听力损失有关。目前有超过150个位点和超过100个基因与非- 综合征性听力损失，然而，很少有候选基因已被确定为复杂的表型， 年龄相关性听力损失（ARHL）或 老年性耳聋， 正变得越来越普遍 年龄一项用于鉴定ARHL相关候选基因的GWAS鉴定了44个独立的基因组， 与听力损失相关的位点。本研究中确定的每个SNP都有一个最近的基因，但这是如何实现的呢？ SNP影响听力损失的基因功能尚未确定。在目标之间建立联系 基因和疾病表型是一个巨大的挑战，最终影响正确的诊断; 在动物模型中基因失活时相似的表型可以为候选基因建立强有力的支持。 我们在斑马鱼中鉴定了44个GWAS候选基因的39个直系同源物，并进一步选择了29个新基因， 将通过以下方式对它们在听力损失中的作用进行功能测试：（1）生成29个（和 旁系同源物）与ARHL相关的候选基因（2）通过高通量表型分析这些突变体 管道，包括形态，细胞和行为表型。确定功能性后果 斑马鱼中候选基因的研究将产生疾病发病机制的见解。