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，影响人口老龄化。通过多次基因组扫描鉴定致病位点，现在开始阐明年龄相关性黄斑变性分子基础的复杂性。 该提案描述了两项基因组扫描的后续工作，一项是基于社区的研究（海狸坝眼科研究），第二项是从我们小组进行的视网膜诊所（家庭年龄相关黄斑病研究）获得的样本。在家庭年龄相关黄斑病研究中，我们有证据表明染色体 15q21 上有一个主要位点（GATA50C03 多点 P = 1.98 x 10[7]；经验 P < 10[-5]；单点 P = 3.6 x 10[-7]）。在我们之前的海狸坝眼研究样本中的ARMD基因组扫描中，该位点作为弱连锁信号存在（D15S659多点P = 0.047），这代表了我们结果的重复。在当前的提案中，我们将通过精细绘制 15q 上的区域来跟进我们的初步结果。 我们提出了分层策略 进行精细绘图，包括验证我们在年龄相关眼病研究的病例和对照样本中的结果。 我们还建议绘制在我们的基因组扫描中显示出正连锁信号的其他基因座。 克隆黄斑变性遗传性基因将增加我们对该疾病过程基本发病机制的了解。 此外，由于我们建议检查病例对照样本，我们将能够获得人群中特定基因引起的可归因风险的初步估计。

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.