Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci

Smith, E. N.; D'Antonio-Chronowska, A.; Greenwald, W. W.; Borja, V.; Aguiar, L. R.; Pogue, R.; Matsui, H.; Borooah, S.; D'Antonio, M.; Ayyagari, R.; Frazer, K. A.

doi:10.1101/440230

bioRxiv · 10.1101/440230

Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci

Smith, E. N.·D'Antonio-Chronowska, A.·Greenwald, W. W.·Borja, V.·Aguiar, L. R.·Pogue, R.·Matsui, H.·Borooah, S.·D'Antonio, M.·Ayyagari, R.·Frazer, K. A.

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Abstract

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.

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Smith, E. N., D'Antonio-Chronowska, A., Greenwald, W. W., Borja, V., Aguiar, L. R., Pogue, R., Matsui, H., Borooah, S., D'Antonio, M., Ayyagari, R., Frazer, K. A.. 2018-10-11. Human iPSC-derived retinal pigment epithelium: a model system for identifying and functionally characterizing causal variants at AMD risk loci. https://doi.org/10.1101/440230

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