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

这项建议建立在密歇根大学科学家之间积极而富有成效的合作基础上 在宾夕法尼亚大学。研究团队为我们的研究做出了几项贡献 了解黄斑变性的遗传学及对一系列统计方法和分析的认识 可用于黄斑变性和其他疾病基因组研究的工具。老年性黄斑 退行性变(AMD)是一种进行性神经退行性疾病，是老年人致盲的主要原因。 老年人。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，很棒 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，重点是一类容易获得的常见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 系统评价DNA序列变异在老年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 不仅是高通量遗传学和基因组学方面的专业知识，而且在开发和 尖端统计和计算方法的应用。通过深层外显子的组合 重新测序和低通全基因组测序我们建议在3,000个样本中描述遗传变异 并评估2000万个基因变异对疾病易感性的贡献，包括不仅 常见的SNPs，但也有罕见的SNPs，短插入缺失多态和较大的拷贝数变异。 我们的方法应该会产生新的黄斑变性易感基因，并提高我们对 在先前涉及的基因座上导致疾病易感性的分子机制。

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.