Advancing Genetics Through the AMDgene Consortium

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是美国50岁以上人群中严重视力丧失的最常见原因，全世界有数百万人患有严重视力丧失。遗传变异对AMD的影响很大，通过最近的技术进步，AMD风险的遗传病因正在被解构。独立研究已经确定并证实了多个基因的变异，这些基因强烈影响AMD的风险，包括CFH，HTRA 1/ARMS 2，C2/CFB和C3，解释了AMD遗传风险的重要部分。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的更温和的个体效应（CFI，LIPC，TIMP 3），与更多的基因座提供暗示性的关联。然而，遗传结构的相当大一部分仍然无法解释，并且缺乏对AMD亚型特异性作用的详细检查。为了解决这些缺陷，需要非常大的样本量的充分表征的情况下，控制和家庭。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。该联盟的最初目标是对现有GWAS数据进行荟萃分析，该数据集包含9，000多例病例和49，000例对照。初步研究发现了新的全基因组显著位点。我们选择了一种在每个研究中心维护原始数据的方法，这种方法促进了所有参与研究中心的持续参与，具有成本和时间效率，并避免了在各种知情同意下共享收集的数据的潜在同意、道德和隐私问题。本提案的主要目标是通过以下具体目标支持AMDgene联盟的工作（1）协调AMDgene联盟的活动;（2）添加新数据集并扩充当前数据集;（3）对现有和新数据集进行详细的荟萃分析;和（4）对这些数据进行详细的二次分析。 公共卫生相关性：视网膜相关性黄斑变性（AMD）是老年人严重视力丧失的最常见原因。多个基因的变异强烈影响AMD的风险，但遗传结构的很大一部分仍然无法解释。AMDgene国际联盟的成立是为了汇总现有的全基因组基因型数据，并进行详细的荟萃分析，以进一步了解AMD的遗传基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the most common cause of severe vision loss among elderly individuals. Variations in multiple genes strongly affect risk to AMD but a substantial portion of the genetic architecture remains unexplained. The AMDgene international consortium was formed to aggregate existing genome-wide genotype data and to perform detailed meta-analyses to further understand the genetic underpinnings of AMD.