Genetic Variation in Age-Related Macular Degeneration

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是60岁以上人群中获得性视力损害的最常见原因。AMD是一种与环境和遗传因素相关的多因素复杂疾病。目前，除了激光光凝疗法可以应用于一小部分具有短期效果的患者之外，没有可靠的治疗选择可用于AMD。尽管在过去几年中进行了协调一致的努力，但AMD遗传决定因素的一般知识并没有实质性进展。该提议的基本假设是，个体病例中对AMD的易感性增加是由许多基因中的细微缺陷的组合引起的，即，从特定的基因型。该提案建议继续我们目前的计划，通过几种方法的组合来破译AMD的遗传原因。其中包括：1）完成AMD患者和匹配对照的大的、临床上和遗传上良好表征的群组（（每个2000个样本）; 2）利用高通量筛选方法，包括我们实验室最近引入的基因分型微阵列，以获得这些人群中遗传异质性的数据;（3）大数字的关联通过统计学分析，获得了AMD中具有特异性（内）表型的衍生基因型（>4百万）; 4）开发动物模型，以进一步确定功能通路中AMD相关的候选基因，并确定遗传研究的功能相关性。我们在这一研究领域的进展和经验表明，一个成功的项目应包括上述所有组成部分。鉴定AMD复杂性状的基因、等位基因、单倍型和基因型，并了解这些缺陷如何促进黄斑变性的发展，有可能改善受影响个体的生活质量。此外，它将使风险个体在发展障碍之前能够准确识别，并有可能改变或预防这种障碍对后代的破坏性视觉后果。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the most common cause of acquired visual impairment in people over the age 60. AMD is a multifactorial, complex disorder associated both with environmental and genetic factors. Currently, no reliable treatment options are available for AMD with the exception of the laser photocoagulation therapy that can be applied to a small fraction of patients with short-term effects. Despite concerted efforts over the last several years, the general knowledge of genetic determinants of AMD has not advanced substantially. The underlying hypothesis of this proposal is that increased susceptibility to AMD in individual cases results from a combination of subtle defects in many genes, i.e., from specific genotype(s). This proposal suggests a continuation of our current program directed towards deciphering the genetic cause of AMD by a combination of several approaches. These include: 1) Completing large, clinically and genetically well-characterized, cohorts of AMD patients and matched controls ((2000 samples each); 2) Utilizing high-throughput screening methods, including recently introduced in our laboratory genotyping microarrays, to obtain data on genetic heterogeneity in these populations; 3) Correlating the large numbers (>4 millions) of derived genotypes with specific (endo-) phenotypes in AMD by statistical analyses; 4) Developing animal models to further define AMD-associated candidate genes in functional pathways and to determine the functional relevance of genetic studies. Our progress and experience in this field of research suggests that a successful project should include all the components listed above. Identification of genes, alleles, haplotypes, and genotypes underlying the AMD complex trait and understanding how these defects contribute to the development of macular degeneration has the potential to improve the quality of life of the affected individuals. Further, it will enable the accurate identification of at-risk individuals before they develop the disorder, and has the potential to modify or prevent the devastating visual consequences of this disorder in future generations.