Integration of eQTL and a single-cell atlas in the human eye identifies causal genes for age-related macular degeneration

Luz D. Orozco, Hsu-Hsin Chen

Age-related Macular Degeneration (AMD) is a leading cause of vision loss. To better understand disease pathogenesis and identify causal genes in GWAS loci for AMD risk, we present a comprehensive database of human retina and retinal pigment epithelium (RPE). Our database comprises macular and non-macular RNA sequencing profiles (RNAseq) from 129 donors, a genome-wide expression quantitative trait loci (eQTL) dataset that includes macula-specific retina and RPE/choroid, and single-nucleus RNAseq (NucSeq) from human retina and RPE with subtype resolution from over 100,000 cells. Using NucSeq, we found enriched expression of AMD candidate genes in RPE cells. We identified 15 putative causal genes for AMD based on co-localization of genetic association signals for AMD risk and eye eQTL, including the genes TSPAN10 and TRPM1. These results demonstrate the value of our human eye database for elucidating genetic pathways, and potential therapeutic targets for ocular diseases.