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。

基本信息

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
项目类别：
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

项目摘要

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且使人衰弱的神经感觉障碍，与听力损失严重相关。生活质量和整体健康。目前它影响着全球 4.3 亿人；预计到 2050 年增加到近 25 亿，导致十分之一的人需要康复。大约50%的病例是预测出来的有遗传基础，但听力损失也可能由其他因素引起，例如年龄、耳毒性药物、噪音、感染或伤害。低成本的下一代测序技术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鉴定出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 100 多个基因与非综合征性听力损失，然而，很少有候选基因被确定用于复杂的表型，例如年龄相关性听力损失（ARHL）或老年性耳聋，其中随着人口的增长而变得越来越普遍年龄。为鉴定与 ARHL 相关的候选基因而进行的 GWAS 鉴定出 44 个独立的基因组与听力损失相关的位点。为本研究中确定的每个 SNP 绘制了一个最近的基因，但这如何 SNP 对听力损失基因功能的影响尚未确定。建立目标之间的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；生成动物模型中基因失活后的相似表型可以为候选基因提供强有力的支持。我们在斑马鱼中鉴定了 44 个 GWAS 候选基因的 39 个直向同源物，并进一步筛选出 29 个新基因将通过以下方式对其在听力损失中的作用进行功能测试：(1) 生成 29 种斑马鱼突变体库（以及 paralogs) 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。识别功能后果对斑马鱼候选基因的研究将产生疾病发病机制的机制见解。