RT Journal Article
SR Electronic
T1 Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 440230
DO 10.1101/440230
A1 Erin N. Smith
A1 Agnieszka D’Antonio-Chronowska
A1 William W. Greenwald
A1 Victor Borja
A1 Lana R. Aguiar
A1 Robert Pogue
A1 Hiroko Matsui
A1 Shyamanga Borooah
A1 Matteo D’Antonio
A1 Radha Ayyagari
A1 Kelly A. Frazer
YR 2018
UL http://biorxiv.org/content/early/2018/10/11/440230.abstract
AB 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 native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observe 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. These results provide insight into the mechanism underlying the association of the VEGFA locus with AMD.