Genome-Wide Targeted Gene Resequencing in Glaucoma

青光眼全基因组靶向基因重测序

• 批准号: 7855323
• 负责人: THERESA GAASTERLAND
• 金额: $ 221.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7855323
• 关键词: Affect; Age; Algorithms; American; Area; Arts; Biological Assay; Blindness; Code; Complement; Computer Analysis; Copy Number Polymorphism; DNA; DNA Resequencing; DNA Sequence Rearrangement; Data; Development; Disease; Disease Association; Disease Management; Disease Progression; Ear; Early Diagnosis; Exons; Eye; Eye diseases; First Degree Relative; Funding; Gene Targeting; General Population; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Glaucoma; Glean; Goals; Grouping; Health Benefit; Heritability; Human Genome; Introns; Knowledge; Laboratories; Libraries; Life Style; Maps; Massachusetts; Measures; Medical; Methods; Monozygotic Twinning; Monozygotic twins; Nature; Open Reading Frames; Pathogenesis; Pathway interactions; Patients; Point Mutation; Predisposition; Prevention; Primary Open Angle Glaucoma; Proteins; Public Health; Rare Diseases; Reaction; Records; Research; Risk; Role; Sampling; Sequence Analysis; Structure; Technology; Testing; Time; Tube; United States; Variant; Visual impairment; Work; base; case control; comparative; design; exome; eye center; genetic variant; genome sequencing; genome wide association study; genome-wide; human disease; improved; innovation; insertion/deletion mutation; member; novel; prevent; public health relevance

DESCRIPTION (provided by applicant): This application responds to the NHGRI's Medical Sequencing Discovery Projects emphasis. Primary open angle glaucoma (POAG) is the most frequent form of glaucoma in the United States and a leading cause of irreversible blindness and visual impairment worldwide. POAG affects more than 2.25 million Americans over age 40. Each year, it causes blindness in ~100,000 Americans and 3 million people worldwide. Treatments for POAG slow progression of the disease but do not reverse glaucomatous damage. Thus, early detection is key in effective management of glaucoma and prevention of further damage. Genetic variation has been shown to have a critical role in the occurrence and development of POAG. The disease has heritability, where first-degree relatives of subjects with POAG have been found to have a risk to develop disease 7-10 times greater than that of the general population, and a high concordance has been observed between monozygotic twins. A number of studies have performed genome-wide scans for glaucoma susceptibility loci and have yielded several loci with POAG association. The number of loci identified provides strong evidence for a polygenic nature of POAG. We propose to study POAG using a novel dual approach: genome-wide targeted gene sequencing complemented by a study of copy number variation in 350 POAG cases and 350 controls. We will leverage two large projects aimed to genotype a large number of POAG cases and controls. The NHGRI-funded GENEVA GLAUGEN consortium is genotyping ~660,000 loci for 2400 samples including 450 POAG cases and 400 controls collected at Massachusetts Eye and Ear Infirmary, and the NEIGHBOR consortium is expected to do the same for ~4000 samples including samples from 600 POAG cases and 600 controls collected at UCSD. While these consortia will discover common loci that increase the risk of POAG, we will take a complementary approach and identify rare variants that may cause POAG. Together, these consortia provide a unique opportunity to blend knowledge gleaned from SNP array data with genome-wide targeted gene sequencing and genome structure data. We will use a novel but proven sequencing strategy to identify coding variants in which all exons with some flanking intron are sequenced, approximately 30 million bases per patient, at 25- times coverage. We will identify point mutations, small insertions and deletions and structural variations, analyze them statistically under the Common Disease Rare Variants (CD-RV) hypothesis, and confirm identified genes and variants in additional patients. The work proposed here uses sequencing technology and computational analysis of sequence data to advance knowledge and understanding of genetic causes of glaucoma, and improve the lifestyle through early diagnosis of the millions that are at risk of being afflicted. PUBLIC HEALTH RELEVANCE: Primary open angle glaucoma (POAG) is the most common form of glaucoma in the United States and a leading cause of irreversible blindness and visual impairment worldwide, affecting more than 2 million Americans over age 40, and causing blindness in ~100,000 Americans and 3 million people worldwide each year. Treatments for the disease can slow progression but do not reverse damage, so early detection is the key for effective disease management and prevention of further damage; so to find genomic variations associated with POAG, a disease with high heritability and with no remedial treatment, this research will use a novel dual approach to genome-wide association study: re-sequence all exons from protein-coding genes in 350 cases and 350 controls, and simultaneously, study copy number variation to find disease-associated single point mutations, small insertions and deletions, and genome structure variations. This research could have considerable public health benefit by identifying genes and their variants associated with pathogenesis of the disease, leading to new strategies for early diagnosis and treatment, inhibition of vision loss, and possibly provide an avenue to prevention.

描述（由申请人提供）：本申请响应NHGRI的医学测序发现项目的重点。原发性开角型青光眼（POAG）是美国最常见的青光眼，也是世界范围内不可逆失明和视力损害的主要原因。POAG影响超过225万40岁以上的美国人。每年，它导致大约10万美国人和全世界300万人失明。POAG的治疗可以减缓疾病的进展，但不能逆转青光眼的损害。因此，早期检测是有效管理青光眼和预防进一步损害的关键。遗传变异在原发性开角型青光眼的发生发展中起着重要作用。该疾病具有遗传性，其中已发现POAG受试者的一级亲属患该病的风险比一般人群高7-10倍，并且在单卵双胞胎之间观察到高度一致性。许多研究已经对青光眼易感性基因座进行了全基因组扫描，并产生了几个与POAG相关的基因座。所鉴定的基因座的数量为POAG的多基因性提供了强有力的证据。我们建议使用一种新的双重方法研究POAG：全基因组靶向基因测序，辅之以350例POAG病例和350例对照的拷贝数变异研究。我们将利用两个大型项目，旨在对大量POAG病例和对照进行基因分型。NHGRI资助的日内瓦GLAUGEN联盟正在对2400份样本进行约660，000个基因座的基因分型，包括在马萨诸塞州眼耳医院收集的450例POAG病例和400例对照，NEIGHBOR联盟预计将对约4000份样本进行同样的分型，包括在UCSD收集的600例POAG病例和600例对照。虽然这些联盟将发现增加POAG风险的常见基因座，但我们将采取互补方法并确定可能导致POAG的罕见变异。总之，这些联盟提供了一个独特的机会，将从SNP阵列数据收集的知识与全基因组靶向基因测序和基因组结构数据相结合。我们将使用一种新的但已被证实的测序策略来识别编码变体，其中所有外显子和一些侧翼内含子都被测序，每个患者大约3000万个碱基，覆盖率为25倍。我们将识别点突变、小插入和缺失以及结构变异，根据常见疾病罕见变异（CD-RV）假设对其进行统计分析，并在其他患者中确认已识别的基因和变异。本文提出的工作使用测序技术和序列数据的计算分析来促进对青光眼遗传原因的认识和理解，并通过早期诊断数百万有患病风险的人来改善生活方式。 公共卫生相关性：原发性开角型青光眼（POAG）是美国最常见的青光眼形式，并且是全球不可逆失明和视力损害的主要原因，影响超过200万40岁以上的美国人，并且每年导致约100，000美国人和全球300万人失明。对该疾病的治疗可以减缓进展，但不能逆转损伤，因此早期检测是有效疾病管理和预防进一步损伤的关键;因此，为了找到与POAG相关的基因组变异，这是一种具有高遗传性且无补救治疗的疾病，本研究将使用一种新的双重方法进行全基因组关联研究：对350例病例和350例对照的蛋白质编码基因的所有外显子进行重新测序，同时研究拷贝数变异，以发现疾病相关的单点突变、小插入和缺失以及基因组结构变异。这项研究可以通过识别与疾病发病机制相关的基因及其变体，产生早期诊断和治疗的新策略，抑制视力丧失，并可能提供预防途径，从而产生相当大的公共卫生效益。

项目成果

Multiple changes in peptide and lipid expression associated with regeneration in the nervous system of the medicinal leech.

• DOI: 10.1371/journal.pone.0018359
• 发表时间: 2011-04-22
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Meriaux C;Arafah K;Tasiemski A;Wisztorski M;Bruand J;Boidin-Wichlacz C;Desmons A;Debois D;Laprévote O;Brunelle A;Gaasterland T;Macagno E;Fournier I;Salzet M
• 通讯作者: Salzet M