Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

The eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 non-ocular human tissues. Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTLs) analyses revealed shared and metabolic condition-specific loci of each type and several eQTLs not previously described in any tissue. Fine mapping of fRPE e/sQTLs across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTLs in a critical ocular cell type to monogenic and complex eye disorders. Examination of 24 fRPE cell lines under glucose and galactose metabolic conditions

眼睛是结构精密复杂的器官，但在大规模功能基因组学数据集（functional genomics datasets）中的代表性却极为有限。视网膜色素上皮（Retinal Pigment Epithelium, RPE）在眼部发育与视网膜稳态维持中发挥着关键作用。我们深入研究了两种代谢条件下培养的人胎儿视网膜色素上皮（fRPE）细胞的基因表达遗传调控特征。在fRPE中表达水平显著偏高的基因显著富集于遗传性眼部疾病相关基因。相较于富集于53种非眼部人体组织的基因附近的遗传变异，这些fRPE特异性基因附近的变异对年龄相关性黄斑变性（age-related macular degeneration, AMD）与近视的发病风险解释度更高。fRPE对谷氨酰胺的线粒体氧化代谢增强，可促进与AMD相关的脂质合成基因的表达。表达与剪接数量性状位点（expression and splice quantitative trait loci, e/sQTLs）分析显示，两类位点分别存在共通位点与代谢条件特异性位点，同时还发现了此前未在任何组织中报道过的多个eQTLs。通过对AMD与近视全基因组关联分析数据中的fRPE e/sQTLs进行精细定位，我们发现了新的候选基因，并揭示了同一RDH5常见变异同时增加AMD发病风险与降低近视发病风险的潜在分子机制。本研究凸显了fRPE独特的转录组学特征，并为关联这一关键眼部细胞类型中的e/sQTLs与单基因及复杂性眼部疾病提供了宝贵的研究资源。本研究同时针对葡萄糖与半乳糖两种代谢条件下的24株fRPE细胞系展开了检测分析。