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

Stem Cell Reports. 2019 Jun 11;12(6):1342-1353. doi: 10.1016/j.stemcr.2019.04.012. Epub 2019 May 9.


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.

Keywords: VEGFA; age-related macular degeneration; chromatin accessibility; fine mapping; genome-wide association; iPSC-RPE; induced pluripotent stem cells; regulatory variants; retinal pigment epithelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Genetic Loci*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Macular Degeneration* / genetics
  • Macular Degeneration* / metabolism
  • Macular Degeneration* / pathology
  • Retinal Pigment Epithelium / metabolism*
  • Retinal Pigment Epithelium / pathology
  • Sequence Analysis, RNA
  • Vascular Endothelial Growth Factor A* / biosynthesis
  • Vascular Endothelial Growth Factor A* / genetics


  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A