Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10− 8), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

中文翻译：

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针对早期年龄相关性黄斑变性的全基因组关联荟萃分析强调了晚期疾病的新位点和见解。


晚期年龄相关性黄斑变性（AMD）是导致失明的主要原因。虽然对晚期 AMD 的基因贡献约有一半已被发现，但人们对早期 AMD 的基因结构知之甚少。为了确定早期 AMD 的遗传因素，我们进行了全基因组关联研究 (GWAS) 荟萃分析（14,034 例病例，91,214 名对照，11 个数据源，包括国际 AMD 基因组联盟、IAMDGC 和英国生物银行、UKBB）。我们通过手动分级 10 个来源的彩色眼底照片以及通过自动机器学习方法对来自 UKBB 的 > 170,000 张照片确定了早期 AMD。我们通过 GWAS 和基于先前建议的 14 个早期 AMD 变体的候选方法搜索了早期 AMD 基因座。总共，我们确定了 10 个对早期 AMD 具有统计显着性的独立位点：(i) 来自 GWAS 的 8 个具有全基因组显着性 (P < 5 × 10− 8)，(ii) 一个先前建议的具有实验显着性的位点 ( P < 0.05/14）在我们的非重叠数据中，并且在结合报告的数据和我们的非重叠数据（总共 17,539 个病例，105,395 个对照）时具有全基因组显着性，以及（iii）另一个先前建议的基因座与实验 -在我们的非重叠数据中具有明智的意义。在这 10 个已识别基因座中，8 个是新基因座，2 个是早期 AMD 已知基因座。 10 个基因座中的大多数与已知的晚期 AMD 基因座（靠近 ARMS2/HTRA1、CFH、C2、C3、CETP、TNFRSF10A、VEGFA、APOE）重叠，但尚未确定对任何 AMD 具有统计显着性的两个基因座除外。在这两个基因座内的 17 个基因中，计算机功能注释表明 CD46 和 TYR 是最有可能的责任基因。 早期 AMD 效应的存在与否区分了晚期 AMD 遗传学的已知途径（补体/脂质途径与细胞外基质代谢）。我们对早期 AMD 的 GWAS 发现了新的位点，强调了早期和晚期 AMD 之间共有和独特的遗传学，并提供了对 AMD 病因学的见解。我们的数据提供的资源与先进 AMD 遗传学的现有 IAMDGC 数据相当，从而能够形成联合观点。早期 AMD 效应能够区分晚期 AMD 的主要途径，强调了这一联合观点的生物学相关性。