Advancing Genetics Through the AMDgene Consortium

摘要 年龄相关性黄斑变性(AMD)是导致个人严重视力丧失的最常见原因 在美国，50岁以上的人有数百万人患有严重的视力丧失。影响 AMD的遗传变异的可能性很大，通过最近的技术进步，AMD风险的遗传病因学 AMD正在被解构。独立研究已经确定并确认了多个基因的变异 这对AMD的风险有很大影响，包括CFH、HTRA1/ARMS2、C2/CFB和C3，解释了 AMD的遗传风险的一部分。全基因组关联研究的初步努力已经确定和/或 确认了另外几个个体效应较小的基因座(CFI、LIPC、TIMP3)，还有更多的基因座 提供提示性联想。然而，遗传结构的很大一部分仍然存在 对AMD亚型的具体影响缺乏解释和详细的检查。致信地址 这些不足之处需要很大的样本量、特征明确的病例和对照以及家系。 在过去的一年里，我们成立了AMDgene财团，将样本和专业知识结合起来。这个 该联盟的最初目标是对9,000多个合并数据集中的现有Gwas数据进行荟萃分析 病例和49,000名对照。初步发现已经确定了新的全基因组显著基因座。我们有 选择了在每个站点维护主要数据的方法，以促进所有站点的持续参与 参与站点，既节省成本又节省时间，并避免潜在的同意、道德和共享隐私问题 在广泛的知情同意下收集的数据。这项提议的主要目标是支持 AMD基因联盟通过以下具体目标努力：(1)协调AMD基因的活动 联盟；(2)增加新的数据集和扩充现有数据集；(3)执行详细的荟萃分析 现有和新的数据集：；和(4)对这些数据进行详细的二次分析。

ABSTRACT Age-related macular degeneration (AMD) is the most common cause of severe vision loss among individuals over age 50 in the U.S. with millions of individuals around the world suffering severe vision loss. The influence of genetic variation on AMD is strong and through recent technological advances the genetic etiology of risk for AMD is being deconstructed. Independent studies have identified and confirmed variations in multiple genes that strongly affect risk to AMD, including CFH, HTRA1/ARMS2, C2/CFB, and C3 explaining a significant portion of the genetic risk for AMD. Initial efforts at genome-wide association studies have identified and/or confirmed several additional loci of more modest individual effect (CFI, LIPC, TIMP3), with many more loci providing suggestive associations. However, a substantial portion of the genetic architecture remains unexplained and detailed examination of effects specific to subtypes of AMD have been lacking. To address these deficiencies very large sample sizes of well characterized cases and controls and families are needed. Over the past year we have formed the AMDgene consortium to combine both samples and expertise. The initial goal of the consortium was a meta-analysis of existing GWAS data in a combined dataset of over 9,000 cases and 49,000 controls. Preliminary findings have identified new genome-wide significant loci. We have chosen an approach that maintains the primary data at each site, which promotes continued engagement by all participating sites, is cost and time efficient, and avoids potential consent, ethics, and privacy issues of sharing data collected under a wide variety of informed consent. The primary goal of this proposal is to support the AMDgene consortium effort through the following specific aims (1) Coordinate the activities of the AMDgene Consortium; (2) Add new datasets and augment current datasets; (3) Perform detailed meta-analyses on existing and new datasets:; and (4) Perform detailed secondary analyses on these data.