Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.

中文翻译：

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基于家族的外显子组测序可识别年龄相关性黄斑变性中的罕见编码变异。

全基因组关联研究 (GWAS) 已在 34 个基因位点上确定了 52 个独立变异，这些变异与年龄相关性黄斑变性 (AMD) 相关，这是全球老年人无法治愈的视力丧失的最常见原因。然而，大多数这些位点的因果基因仍然未知。在这项研究中，我们对来自 63 个患有 AMD 的多重家族的 264 名个体进行了全外显子组测序，并分析了 AMD 相关位点候选靶基因中罕见的蛋白质改变变异的数据。在三个或更多家族的CFH、PUS7、RXFP2、PHF12和TACC2基因中发现了罕见的编码变体。此外，我们在C9 中检测到罕见的编码变异，SPEF2和BCAR1基因，以前被认为是各自 AMD 易感基因座的可能致病基因。在我们的研究中，CFH和C9基因中罕见变异的鉴定证实了先前关于 AMD 补体途径基因中罕见变异的报道。然后，我们扩展了我们的外显子组分析，并在三个或更多家族的 AMD-GWAS 基因座之外的 13 个基因中发现了罕见的蛋白质改变变体。这些基因中的两个，SCN10A和KIR2DL4，因为这些基因中的变异在病例对照队列中也显示出与 AMD 的关联，尽管不是在全基因组显着性水平上。我们的研究首次对 AMD 中的罕见变异进行了大规模、全外显子组分析。此处报道的候选靶基因的进一步独立复制和分子研究将有助于获得对 AMD 发病机制潜在机制的新见解。