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

doi:10.1016/j.celrep.2019.12.082

Integration of eQTL and a Single-Cell Atlas in the Human Eye Identifies Causal Genes for Age-Related Macular Degeneration

Cell Rep. 2020 Jan 28;30(4):1246-1259.e6. doi: 10.1016/j.celrep.2019.12.082.

Authors

Luz D Orozco¹, Hsu-Hsin Chen², Christian Cox³, Kenneth J Katschke Jr³, Rommel Arceo⁴, Carmina Espiritu⁴, Patrick Caplazi⁴, Sarajane Saturnio Nghiem⁴, Ying-Jiun Chen⁵, Zora Modrusan⁵, Amy Dressen⁶, Leonard D Goldstein⁷, Christine Clarke¹, Tushar Bhangale⁶, Brian Yaspan⁶, Marion Jeanne³, Michael J Townsend⁸, Menno van Lookeren Campagne⁹, Jason A Hackney¹⁰

Affiliations

¹ Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA.
² Department of Biomarker Discovery OMNI, Genentech, South San Francisco, CA 94080, USA.
³ Department of Immunology Discovery, Genentech, South San Francisco, CA 94080, USA.
⁴ Department of Pathology, Genentech, South San Francisco, CA 94080, USA.
⁵ Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
⁶ Department of Human Genetics, Genentech, South San Francisco, CA 94080, USA.
⁷ Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA; Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
⁸ Department of Biomarker Discovery OMNI, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].
⁹ Department of Immunology Discovery, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].
¹⁰ Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080, USA. Electronic address: [email protected].

PMID: 31995762
DOI: 10.1016/j.celrep.2019.12.082

Abstract

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.

Keywords: AMD; GWAS; NucSeq; RNA-seq; age-related macular degeneration; eQTL; retina; retinal pigment epithelium; single cell.

MeSH terms

Aged
Aged, 80 and over
Alleles
Choroid / metabolism
Databases, Genetic
Disease Susceptibility / metabolism*
Female
Gene Expression Regulation / genetics*
Genome-Wide Association Study
Humans
Macular Degeneration / genetics
Macular Degeneration / metabolism*
Male
Middle Aged
Polymorphism, Single Nucleotide
Quantitative Trait Loci
RNA-Seq
Retinal Pigment Epithelium / metabolism*
Risk Factors
Single-Cell Analysis
TRPM Cation Channels / genetics
TRPM Cation Channels / metabolism
Tetraspanins / genetics
Tetraspanins / metabolism
Transcriptome / genetics

Substances

TRPM Cation Channels
TRPM1 protein, human
TSPAN10 protein, human
Tetraspanins