Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci.

Stem Cell Reports

Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Cellular and Molecular Medicine East, 9500 Gilman Drive #0761, La Jolla, CA 92093-0761, USA. Electronic address:

Published: June 2019

We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565613PMC
http://dx.doi.org/10.1016/j.stemcr.2019.04.012DOI Listing

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