Fine Mapping of Genes for Age-Related Maculopathy

描述（由申请人提供）：黄斑变性是西方世界失明的主要原因，影响老年人口。年龄相关性黄斑变性的分子基础的复杂性现在开始被阐明，通过多个基因组扫描识别致病基因座。 该提案描述了两次基因组扫描的后续行动，一次是基于社区的研究（比弗坝眼科研究），第二次是我们小组进行的从视网膜诊所获得的样本（家庭年龄相关黄斑病变研究）。在家族年龄相关性黄斑病变研究中，我们有证据表明染色体15 q21上存在一个主要基因座（GATA 50 C 03多点P = 1.98 x 10[7];经验P < 10[-5];单点P = 3.6 x 10[-7]）。该基因座在我们之前的比弗坝眼部研究样本中的ARMD基因组扫描中作为弱连锁信号存在（D15 S659多点P=0.047），这代表了我们结果的重复。在当前的提议中，我们将通过精细映射15 q上的区域来跟踪我们的初步结果。 我们提出了一个分层战略， 进行精细的映射，包括验证我们的结果在一个样本的情况下，并控制从视网膜相关眼病研究。 我们还建议映射其他基因座，在我们的基因组扫描中表现出积极的连锁信号。 遗传性黄斑变性基因的克隆将增加我们对疾病过程的基本发病机制的理解。 此外，由于我们建议检查病例对照样本，我们将能够获得归因于人群中特定基因的风险的初步估计。

DESCRIPTION (provided by applicant): Macular degeneration is a leading cause of blindness in the Western World that affects the aging population. The complexity of the molecular basis of age-related macular degeneration is now beginning to be elucidated with the identification of disease-causing loci through multiple genome scans. This proposal describes a follow-up to two genome scans, one on a community based study (The Beaver Dam Eye Study) and the second in sample obtained from a Retinal Clinic (The Family Age Related Maculopathy Study) conducted by our group. We have evidence of a major locus on chromosome 15q21 (GATA50C03 multipoint P = 1.98 x 10[7]; empirical P < 10[-5]; singlepoint P = 3.6 x 10[-7]) in the Family Age Related Maculopathy Study. This locus was present as a weak linkage signal in our previous ARMD genome scan in the Beaver Dam Eye Study sample (D15S659 multipoint P=0.047), which represents a replication of our results. In the current proposal we will follow up our initial results by fine mapping the region on 15q. We have presented a tiered strategy to perform fine mapping, including validating our results in a sample of cases and controls from the Age-Related Eye Disease Study. We also propose to map other loci that demonstrated positive linkage signals in our genome scan. The cloning of genes for the heritable forms of macular degeneration will increase our understanding of the basic pathogenesis of the disease process. Further, since we propose to examine a case control sample, we will be able to obtain initial estimates of attributable risk due to a particular gene in the population.