Key result
Genetic analysis links a common RDH5 variant to higher AMD risk and lower myopia risk.
Why the study?
The retinal pigment epithelium plays vital roles in ocular development and retinal homeostasis, but large-scale functional genomics data for the eye are limited.
The study highlights the unique transcriptomic characteristics of human fetal RPE and provides a resource connecting e/sQTLs to monogenic and complex eye disorders like AMD and myopia.
May guide prioritization of fRPE-selective variants in ocular disease genetics; leaves open clinical translation and in vivo validation.
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 other 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/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL 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/sQTL in a critical ocular cell type to monogenic and complex eye disorders.
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Liu et al. (2018) studied Ocular diseases (Age-related macular degeneration, myopia) (n=23). Metabolic conditions (glucose vs galactose) and genetic variation was evaluated on Expression and splice quantitative trait loci (e/sQTL) discovery and colocalization with ocular disease GWAS. Genetic analysis of human fetal retinal pigment epithelium cells identified 726 shared, 272 glucose-specific, and 191 galactose-specific eQTLs, revealing that a common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk.
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