Defining early-onset glaucomagenetic etiologies

定义早发性青光眼病因

基本信息

批准号：
10249270
负责人：
Janey L Wiggs
金额：
$ 70.74万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10249270
关键词：
ANGPT1 gene Adult Affect Age Alleles Australia Blindness Cells Child Clinical Code Collaborations Collection Complex Copy Number Polymorphism Data Detection Development Diagnostic tests Disease Enhancers Ensure Etiology Exhibits FOXC1 gene Family Family member Funding Gene Expression Regulation Gene Frequency Genes Genetic Counseling Genetic Predisposition to Disease Genetic Variation Genetic study Genome Genomics Glaucoma Goals Individual International Knowledge Length Methods MicroRNAs Modeling Molecular Diagnosis Mus Mutation Nature Oligogenic Traits Online Systems Onset of illness Pathogenicity Pathway Analysis Pathway interactions Patients Pattern Population Primary Open Angle Glaucoma Process Promoter Regions Quality Control RNA Splicing Structure Testing Untranslated RNA Variant Work Zebrafish base blind causal variant clinical care curative treatments disorder risk early onset exome sequencing experience gain of function gene therapy genetic element genetic variant genome sequencing genome wide association study improved insertion/deletion mutation loss of function multi-ethnic novel online resource polygenic risk score proband rare variant risk prediction risk variant screening segregation therapeutic target whole genome young adult

项目摘要

Project Summary Glaucoma is a clinically and genetically complex disease that is the leading cause of irreversible blindness worldwide. The disease exhibits both complex and Mendelian inheritance with complex disease more common in adult populations and Mendelian forms more common in children and young adults. While recent genome- wide association studies (GWAS) have identified >100 risk loci for adult-onset disease, only 10 genes are known to cause early-onset glaucoma (EOG, glaucoma developing before age 40), and few studies have targeted this severely affected population. The current set of EOG genes can explain only 20% of cases, leaving most affected individuals without a molecular diagnosis. Treatment options for EOG cases are limited and these patients are most likely to become blind during their lifetimes. The overall goal of this proposal is to discover novel EOG causal genes that will provide opportunities for gene-based screening and diagnostic tests, allowing for improved risk prediction and genetic counseling, as well as new, and potentially curative, therapeutic targets. The current lack of EOG genes creates a pressing need to study genetic variation across the full length of the genome in these severely affected glaucoma cases. Using whole genome sequencing (WGS) we will create a comprehensive set of variants for genomic analyses for two large collections of clinically well-characterized early-onset glaucoma probands and families through a collaboration between the USA and Australia. We will accomplish the following specific aims: 1) Comprehensively identify all genetic variants in at least 1000 EOG probands and selected family members using high quality WGS data and robust variant calling and annotation pipelines; 2) Discover novel highly penetrant genetic variants in novel causative genes in EOG patients and families; and 3) Examine oliogogenic inheritance and assess relationships of EOG genes with adult-onset disease (primary open angle glaucoma).

项目概要青光眼是一种临床和遗传复杂的疾病，是导致不可逆失明的主要原因全世界。该疾病表现出复杂遗传和孟德尔遗传，复杂疾病更为常见在成年人群中，孟德尔形式在儿童和年轻人中更常见。虽然最近的基因组- 广泛关联研究 (GWAS) 已识别出超过 100 个成人发病疾病的风险位点，但仅 10 个基因被确定已知会导致早发性青光眼（EOG，40 岁之前发生青光眼），但很少有研究表明针对这些受到严重影响的人群。目前的EOG基因组只能解释20%的病例，使大多数受影响的个体无法进行分子诊断。 EOG 病例的治疗选择有限这些患者一生中最有可能失明。该提案的总体目标是发现新的 EOG 致病基因，这将为基于基因的筛查和诊断提供机会测试，可以改进风险预测和遗传咨询，以及新的、潜在的治疗方法，治疗目标。目前 EOG 基因的缺乏迫切需要研究跨物种的遗传变异这些严重影响青光眼病例的基因组全长。使用全基因组测序（WGS）我们将为两个大型集合创建一套全面的变体用于基因组分析通过与美国和澳大利亚。我们将完成以下具体目标： 1）全面识别所有基因使用高质量的 WGS 数据和稳健的方法，在至少 1000 名 EOG 先证者和选定的家庭成员中发现变异变体调用和注释管道； 2）在新的致病原因中发现新的高渗透性遗传变异 EOG患者及其家属的基因； 3) 检查寡源遗传并评估 EOG 的关系与成人发病的疾病（原发性开角型青光眼）相关的基因。