Defining early-onset glaucomagenetic etiologies

项目摘要 青光眼是一种临床和遗传复杂的疾病，是导致不可逆性失明的主要原因。 全世界。该病表现为复杂遗传和孟德尔遗传，其中复杂疾病更为常见 成人型和孟德尔型多见于儿童和青壮年。而最近的基因组- 广谱关联研究已经确定了100个成人发病的风险基因，只有10个基因是 已知会导致早发性青光眼(EOG，40岁之前发展的青光眼)，但很少有研究 针对这一严重受影响的人群。目前的EOG基因只能解释20%的病例， 使大多数受影响的人得不到分子诊断。EOG病例的治疗选择有限 而这些患者在他们的一生中最有可能失明。这项提案的总体目标是 发现新的EOG原因基因，将为基于基因的筛查和诊断提供机会 测试，允许改进的风险预测和遗传咨询，以及新的和潜在的治愈， 治疗靶点。目前缺乏EOG基因，迫切需要研究跨性别的遗传变异。 这些严重青光眼患者的基因组全长。使用全基因组测序 (WGS)我们将创建一套全面的变种，用于两个大型集合的基因组分析 临床特征良好的早发性青光眼先证者和家庭 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 至少1000名EOG先证者和选定家庭成员的变种使用高质量的WGS数据和稳健 变种调用和注解管道；2)发现新的高渗透性基因变种 EOG患者和家系的基因；以及3)检查EOG的成骨遗传和评估EOG的关系 成人发病的基因(原发开角型青光眼)。

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).