More Complete Assessment of DNA Variation in Age-Related Macular Degeneration

更全面地评估年龄相关性黄斑变性中的 DNA 变异

基本信息

批准号：
8727560
负责人：
Goncalo Abecasis
金额：
$ 114.85万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727560
关键词：
Accounting Affect Age Age related macular degeneration Biological Biology Biometry Blindness Cataloging Catalogs Cataract Clinical Code Collaborations Complex Computing Methodologies Copy Number Polymorphism DNA DNA Resequencing DNA Sequence DNA Sequence Analysis Data Data Analyses Deposition Development Disease Disease Outcome Disease susceptibility Early Diagnosis Elderly Ensure Frequencies Genes Genetic Genetic Polymorphism Genetic Variation Genome Genome Scan Genomics Genotype Individual Knowledge Lead Macular degeneration Methods Michigan Molecular Neurodegenerative Disorders Ophthalmology Pathogenesis Pennsylvania Population Predisposition Quality of life Research Research Personnel Role Scientist Single Nucleotide Polymorphism Statistical Methods TIMP3 gene Technology United States Universities Variant analytical tool chemotactic factor inactivator complement pathway design disorder prevention disorder risk exome genetic variant genome sequencing genome wide association study genotyping technology improved insertion/deletion mutation insight next generation sequencing rare variant repository therapy development tool trait

项目摘要

This proposal builds on active and productive collaboration between scientists at the University of Michigan and at the University of Pennsylvania. The research team has made several contributions both to our understanding of the genetics of macular degeneration and to the array of statistical methods and analytical tools available for genomic studies of macular degeneration and other disorders. Age-related macular degeneration (AMD) is a progressive neurodegenerative disease and the major cause of blindness among the elderly. Loss of vision caused by macular degeneration is currently irreversible. In the past several years, great progress has been made in our understanding of the molecular mechanisms that lead to macular degeneration through SNP genotyping studies, which focus on an easily accessible class of common DNA sequence variants. Here, we propose to use advances in DNA sequencing and genotyping technology to more systematically evaluate the role of DNA sequence variation in susceptibility to age related macular degeneration. Our research team includes not only clinical expertise and understanding of macular degeneration but also expertise in high-throughput genetics and genomics and in the development and application of cutting edge statistical and computational methods. Through a combination of deep exome resequencing and low pass whole genome sequencing we propose to characterize genetic variation in 3,000 individuals and evaluate the contribution of >20M genetic variants to disease susceptibility, including not only common SNPs, but also rare SNPs, short insertion deletion polymorphisms, and larger copy number variants. Our approach should yield new susceptibility loci for macular degeneration and improve our understanding of the molecular mechanisms that contribute to disease susceptibility in previously implicated loci.

该提案建立在密歇根大学科学家之间积极和富有成效的合作基础上和宾夕法尼亚大学。该研究团队为我们的研究做出了多项贡献了解黄斑变性的遗传学以及一系列统计方法和分析可用于黄斑变性和其他疾病的基因组研究的工具。年龄相关性黄斑变性（AMD）是一种进行性神经退行性疾病，也是导致失明的主要原因老年。黄斑变性导致的视力丧失目前是不可逆转的。在过去的几年里，伟大我们对导致黄斑变性的分子机制的理解取得了进展通过 SNP 基因分型研究，重点关注一类易于获取的常见 DNA 序列变种。在这里，我们建议利用 DNA 测序和基因分型技术的进步来更多地系统评估 DNA 序列变异在年龄相关性黄斑易感性中的作用退化。我们的研究团队不仅包括临床专业知识和对黄斑的了解变性，还包括高通量遗传学和基因组学以及开发和基因组学方面的专业知识应用尖端统计和计算方法。通过深层外显子组的组合我们建议通过重测序和低通全基因组测序来表征 3,000 个基因组中的遗传变异个体并评估 >20M 遗传变异对疾病易感性的贡献，不仅包括常见的 SNP，还有罕见的 SNP、短插入缺失多态性和较大拷贝数变异。我们的方法应该产生黄斑变性的新易感位点并提高我们对黄斑变性的理解导致先前涉及的基因座疾病易感性的分子机制。