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人类胎儿视网膜色素上皮基因表达的遗传分析提示眼病发病机制。

Genetic analyses of human fetal retinal pigment epithelium gene expression suggest ocular disease mechanisms.

机构信息

1Department of Biology, Stanford University, Stanford, CA 94305 USA.

2Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA.

出版信息

Commun Biol. 2019 May 20;2:186. doi: 10.1038/s42003-019-0430-6. eCollection 2019.

DOI:10.1038/s42003-019-0430-6
PMID:31123710
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6527609/
Abstract

The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis but has limited representation in large-scale functional genomics datasets. Understanding how common human genetic variants affect RPE gene expression could elucidate the sources of phenotypic variability in selected monogenic ocular diseases and pinpoint causal genes at genome-wide association study (GWAS) loci. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions and discovered hundreds of shared or condition-specific expression or splice quantitative trait loci (e/sQTLs). Co-localizations of fRPE e/sQTLs with age-related macular degeneration (AMD) and myopia GWAS data suggest new candidate genes, and mechanisms by which a common allele 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.

摘要

视网膜色素上皮 (RPE) 在眼部发育和视网膜稳态中起着至关重要的作用，但在大规模功能基因组学数据集中的代表性有限。了解常见的人类遗传变异如何影响 RPE 基因表达，可以阐明在选定的单基因眼部疾病中表型变异的来源，并确定全基因组关联研究 (GWAS) 位点的因果基因。我们研究了在两种代谢条件下培养的人胎儿 RPE (fRPE) 细胞的基因表达遗传学，发现了数百个共同或条件特异性表达或剪接数量性状基因座 (e/sQTLs)。fRPE e/sQTLs 与年龄相关性黄斑变性 (AMD) 和近视 GWAS 数据的共定位提示了新的候选基因，以及常见等位基因如何既增加 AMD 风险又降低近视风险的机制。我们的研究强调了 fRPE 的独特转录组特征，并提供了一种资源，将关键眼部细胞类型中的 e/sQTLs 与单基因和复杂眼部疾病联系起来。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/7c3809597e4b/42003_2019_430_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/16a79cb0369f/42003_2019_430_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/7c3809597e4b/42003_2019_430_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/16a79cb0369f/42003_2019_430_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/c421c0e3af19/42003_2019_430_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/0fd52b8edf69/42003_2019_430_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/b0db7d233351/42003_2019_430_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c75e/6527609/7c3809597e4b/42003_2019_430_Fig5_HTML.jpg

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