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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和使人衰弱的神经感觉障碍，与大量减少有关