Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.
PLoS One. 2018 Mar 12;13(3):e0194321. doi: 10.1371/journal.pone.0194321. eCollection 2018.
Late-stage age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly with a complex etiology. The most important non-modifiable risk factors for onset and progression of late AMD are age and genetic risk factors, however, little is known about the interplay between genetics and age or sex. Here, we conducted a large-scale age- and sex-stratified genome-wide association study (GWAS) using 1000 Genomes imputed genome-wide and ExomeChip data (>12 million variants). The data were established by the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) from 16,144 late AMD cases and 17,832 controls. Our systematic search for interaction effects yielded significantly stronger effects among younger individuals at two known AMD loci (near CFH and ARMS2/HTRA1). Accounting for age and gene-age interaction using a joint test identified two additional AMD loci compared to the previous main effect scan. One of these two is a novel AMD GWAS locus, near the retinal clusterin-like protein (CLUL1) gene, and the other, near the retinaldehyde binding protein 1 (RLBP1), was recently identified in a joint analysis of nuclear and mitochondrial variants. Despite considerable power in our data, neither sex-dependent effects nor effects with opposite directions between younger and older individuals were observed. This is the first genome-wide interaction study to incorporate age, sex and their interaction with genetic effects for late AMD. Results diminish the potential for a role of sex in the etiology of late AMD yet highlight the importance and existence of age-dependent genetic effects.
晚期年龄相关性黄斑变性（AMD）是老年人视力障碍的主要原因，其病因复杂。发病和晚期 AMD 进展最重要的不可改变的危险因素是年龄和遗传危险因素，但遗传因素与年龄或性别之间的相互作用知之甚少。在这里，我们使用 1000 个基因组导入的全基因组和外显子组芯片数据（>1200 万个变体）进行了大规模的年龄和性别分层全基因组关联研究（GWAS）。这些数据是由国际年龄相关性黄斑变性基因组学联合会（IAMDGC）从 16144 例晚期 AMD 病例和 17832 例对照中建立的。我们系统地搜索了相互作用效应，在两个已知的 AMD 基因座（CFH 附近和 ARMS2/HTRA1）中，在年轻个体中发现了明显更强的效应。使用联合检验来解释年龄和基因年龄相互作用，与之前的主要效应扫描相比，鉴定出了两个额外的 AMD 基因座。其中一个是在视网膜簇蛋白样蛋白（CLUL1）基因附近的新的 AMD GWAS 基因座，另一个在视黄醛结合蛋白 1（RLBP1）附近，该基因座是在核和线粒体变体的联合分析中最近确定的。尽管我们的数据具有相当大的效力，但没有观察到性别依赖性效应或年轻个体和老年个体之间方向相反的效应。这是第一项纳入年龄、性别及其与晚期 AMD 遗传效应相互作用的全基因组相互作用研究。结果降低了性别在晚期 AMD 发病机制中的作用潜力，但突出了年龄依赖性遗传效应的重要性和存在性。
