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

描述（由申请人提供）：本提案建立在密歇根大学和宾夕法尼亚大学科学家之间积极和富有成效的合作基础上。该研究小组对我们对黄斑变性的遗传学的理解以及对黄斑变性和其他疾病的基因组研究的统计方法和分析工具的阵列做出了一些贡献。年龄相关性黄斑变性（AMD）是一种进行性神经退行性疾病，是老年人失明的主要原因。目前由黄斑变性引起的视力丧失是不可逆转的。在过去的几年中，通过SNP基因分型研究，我们对导致黄斑变性的分子机制的理解取得了很大进展，这些研究主要集中在一类容易获得的常见DNA序列变异上。在此，我们建议利用DNA测序和基因分型技术的进展来更系统地评估DNA序列变异在年龄相关性黄斑变性易感性中的作用。我们的研究团队不仅包括临床专业知识和对黄斑变性的理解，还包括高通量遗传学和基因组学以及尖端统计和计算方法的开发和应用方面的专业知识。通过深度外显子组重测序和低通全基因组测序的结合，我们拟对3000个个体的遗传变异进行表征，并评估>20M遗传变异对疾病易感性的贡献，这些变异不仅包括常见的snp，还包括罕见的snp、短插入缺失多态性和大拷贝数变异。我们的方法将产生新的黄斑变性易感性位点，并提高我们对先前涉及位点的疾病易感性的分子机制的理解。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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. Previous genetic studies of age-related macular degeneration focused on a class of easily accessible DNA sequence variants. We have assembled a team of experts in the clinical features of age related macular degeneration, in the methods and tools for the analysis of DNA sequence variation, and in associated computational problems and propose to more thoroughly assess the contribution of DNA sequence variation to disease susceptibility. We expect our research will lead to new disease susceptibility variants and better understanding of the molecular changes that lead to disease. This knowledge will facilitate development of new therapies and development of strategies for early diagnosis and prevention of disease.