Fine Mapping of Genes for Age-Related Maculopathy

描述(申请人提供)：黄斑变性是西方世界影响老龄化人口的主要失明原因。老年性黄斑变性分子基础的复杂性现在开始随着通过多基因组扫描识别致病基因而被阐明。这项建议描述了两项基因组扫描的后续行动，一项是基于社区研究(Beaver Dam Eye研究)，另一项是从我们团队进行的视网膜诊所(家庭年龄相关性黄斑病变研究)获得的样本中。在家族性老年性黄斑病变研究中，我们发现了位于染色体15q21(GATA50C03多点P=1.98 x 10[7]；经验性P&lt；10[-5]；单点P=3.6 x 10[-7])上的一个主要基因座。该基因座作为弱连锁信号出现在我们之前在河狸大坝眼科研究样本(D15S659多点P=0.047)中进行的ARMD基因组扫描中，这代表了我们结果的重复。在目前的提案中，我们将通过精细绘制15q上的区域来跟进我们的初步结果。我们已经提出了一个分层战略 进行精细绘图，包括在年龄相关眼病研究的病例和对照样本中验证我们的结果。我们还建议在我们的基因组扫描中定位其他显示阳性连锁信号的基因座。黄斑变性遗传型基因的克隆将增加我们对疾病过程的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，我们将能够获得由于人群中的特定基因而导致的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.