Advancing Genetics Through the AMDgene Consortium

摘要 视网膜相关性黄斑变性（AMD）是个体中严重视力丧失的最常见原因 在美国，50岁以上的人患有严重的视力丧失，世界各地有数百万人患有严重的视力丧失。的影响 AMD的遗传变异是强大的，通过最近的技术进步， AMD正在被解构。独立的研究已经确定并证实了多个基因的变异 强烈影响AMD的风险，包括CFH，HTRA 1/ARMS 2，C2/CFB和C3，解释了一个显著的 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 证实了几个额外的基因座更温和的个体效应（CFI，LIPC，TIMP 3），与更多的基因座 提供暗示性的联想。然而，遗传结构的很大一部分仍然存在， 缺乏对AMD亚型的特异性作用的无法解释的和详细的研究。解决 这些缺陷需要非常大的样本量的良好表征的病例和对照以及家族。 在过去的一年里，我们成立了AMDgene联盟，将样本和专业知识联合收割机结合起来。的 该联盟的最初目标是对现有的GWAS数据进行荟萃分析，这些数据来自一个超过9000个的综合数据集 病例组和对照组49,000例。初步研究发现了新的全基因组显著位点。我们有 选择了一种在每个站点维护原始数据的方法，以促进所有人的持续参与 参与网站，是成本和时间效率，并避免潜在的同意，道德和隐私问题的共享 在各种知情同意下收集的数据。该提案的主要目标是支持 AMDgene联盟通过以下具体目标开展工作：（1）协调AMDgene的活动 联盟;（2）添加新的数据集并扩充当前数据集;（3）对以下内容进行详细的荟萃分析 现有的和新的数据集;以及（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.