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,
Christian Cox,
Kenneth J. Katschke, Jr.,
Rommel Arceo,
Carmina Espiritu,
Patrick Caplazi,
Sarajane Saturnio Nghiem,
Ying-Jiun Chen,
Zora Modrusan,
Amy Dressen,
Leonard D. Goldstein,
Christine Clarke,
Tushar Bhangale,
Brian Yaspan,
Marion Jeanne,
Michael J. Townsend,
Menno van Lookeren Campagne,
Jason A. Hackney
Affiliations
Luz D. Orozco
Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA
Hsu-Hsin Chen
Department of Biomarker Discovery OMNI, Genentech, South San Francisco, CA 94080, USA
Christian Cox
Department of Immunology Discovery, Genentech, South San Francisco, CA 94080, USA
Kenneth J. Katschke, Jr.
Department of Immunology Discovery, Genentech, South San Francisco, CA 94080, USA
Rommel Arceo
Department of Pathology, Genentech, South San Francisco, CA 94080, USA
Carmina Espiritu
Department of Pathology, Genentech, South San Francisco, CA 94080, USA
Patrick Caplazi
Department of Pathology, Genentech, South San Francisco, CA 94080, USA
Sarajane Saturnio Nghiem
Department of Pathology, Genentech, South San Francisco, CA 94080, USA
Ying-Jiun Chen
Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA
Zora Modrusan
Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA
Amy Dressen
Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA
Leonard D. Goldstein
Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA; Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA
Christine Clarke
Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA
Tushar Bhangale
Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA
Brian Yaspan
Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA
Marion Jeanne
Department of Immunology Discovery, Genentech, South San Francisco, CA 94080, USA
Michael J. Townsend
Department of Biomarker Discovery OMNI, Genentech, South San Francisco, CA 94080, USA; Corresponding author
Menno van Lookeren Campagne
Department of Immunology Discovery, Genentech, South San Francisco, CA 94080, USA; Corresponding author
Jason A. Hackney
Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA; Corresponding author
Summary: 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 (RNA-seq) profiles from 129 donors, a genome-wide expression quantitative trait loci (eQTL) dataset that includes macula-specific retina and RPE/choroid, and single-nucleus RNA-seq (NucSeq) from human retina and RPE with subtype resolution from more than 100,000 cells. Using NucSeq, we find enriched expression of AMD candidate genes in RPE cells. We identify 15 putative causal genes for AMD on the basis of 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. : To find genes underlying risk for age-related macular degeneration, Orozco et al. analyze human ocular transcriptomes in conjunction with genotypes and build a single-nucleus atlas. They identify 15 putative causal genes, of which TSPAN10 and TRPM1 were enriched in retinal pigment epithelium, the site of early disease pathology. Keywords: eQTL, NucSeq, single cell, RNA-seq, age-related macular degeneration, AMD, retinal pigment epithelium, retina, GWAS
