Defining early-onset glaucomagenetic etiologies

项目摘要 青光眼是一种临床和遗传学上复杂的疾病，是导致不可逆失明的主要原因 国际吧该疾病表现出复杂和孟德尔遗传，复杂疾病更常见 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）已经确定了>100个成人发病的风险基因座，只有10个基因是 已知会导致早发性青光眼（EOG，40岁之前发生的青光眼），很少有研究 针对这些受影响严重的人群。目前的EOG基因组只能解释20%的病例， 使得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 这些病人很可能在他们的一生中失明。本提案的总体目标是 发现新的EOG致病基因，为基于基因的筛查和诊断提供机会 测试，允许改善风险预测和遗传咨询，以及新的，和潜在的治疗， 治疗目标目前缺乏EOG基因，迫切需要研究跨性别的遗传变异。 这些严重青光眼病例的基因组全长。使用全基因组测序 (WGS)我们将创建一个全面的变异基因组分析的两个大集合， 临床特征良好的早发性青光眼先证者和家庭通过合作之间的 美国和澳大利亚。我们将实现以下具体目标：1）全面识别所有遗传 至少1000个EOG先证者和选定的家族成员中的变异，使用高质量的WGS数据和稳健的 变异调用和注释管道; 2）在新致病性中发现新的高度渗透性遗传变异 EOG患者和家族中的基因; 3）检查寡基因遗传并评估EOG的关系 成人发病性青光眼（原发性开角型青光眼）的基因。

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).