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.

听力丧失是一种高度普遍且令人衰弱的神经感觉障碍生活质量和整体健康。目前，它影响了全球4.3亿人；到2050年，这预计将增加到近25亿，并导致10人需要康复。预计约有50％的病例为了有遗传基础，但是听力损失也可能是由年龄，耳毒性药物等其他因素引起的噪音，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协会研究（GWAS）和外显子组测序项目已经确定了数百种变体和基因与听力损失有关。目前有150多个基因座和超过100个基因与非 - 综合性听力损失，但是很少有候选基因被鉴定为复杂的表型，例如与年龄有关的听力损失（ARHL）或 Presbycusis，哪个随着人口的越来越普遍年龄。用于识别与ARHL相关的候选基因的GWA鉴定了44个独立基因组与听力损失相关的基因座。为本研究中鉴定的每个SNP映射了一个最近的基因，但是如何 SNP影响听力损失中的基因功能。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。生成动物模型中基因失活的类似表型可以为候选基因建立强大的支持。我们确定了斑马鱼中44个GWAS候选基因的39个直系同源物，并进一步选择了29个新型基因（1）生成29（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学，细胞和行为表型。确定功能后果斑马鱼中的候选基因将产生疾病发病机理的机理见解。