Genetic disorders impacting vision affect millions of individuals worldwide, including age-related macular degeneration (common) and inherited retinal disorders (rare). There is incomplete understanding of the impact of genetic variation on gene expression in the human retina, and its role in genetic disorders. Through the generation of whole genome sequencing and bulk RNA-sequencing of neurosensory retina (NSR) and retinal pigment epithelium (RPE) from 201 post-mortem eyes, we uncovered common and rare genetic variants shaping retinal expression profiles. This includes 1,483,595 significant cis-expression quantitative trait loci (eQTLs) impacting 9,959 and 3,699 genes in NSR and RPE, respectively, with associated genetic variants enriched to cis-candidate regulatory elements and notable shared eGenes between NSR and RPE. We also detected 1051 expression outliers and prioritised 299 rare non-coding single-nucleotide, structural variants or copy number variants as plausible drivers for 28% of outlier events. This study increases understanding of gene expression regulation in the human retina.

The authors have declared no competing interest.

This research was supported by the Macular Society (United Kingdom), Fight For Sight, the UK Medical Research Council and the NIHR Manchester Biomedical Research Centre (NIHR203308). This work has also been supported by the Wellcome Trust (224643/Z/21/Z, Clinical Research Career Development Fellowship, P.I.S), the UK National Institute for Health Research (NIHR) Clinical Lecturer Programme (CL-201-06-001, P.I.S), the NIHR Research Professorship grant (RP-2016-07-011, DB) and the NIH/NEI (R01 EY031424 to A.V.S and R01EY035717 to K.M.B.). The views expressed are those of the authors and not necessarily those of the funders, including the NIHR and the Department of Health and Social Care.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Donor eye tissues were obtained from the Manchester Eye Tissue Repository, an ethically approved Research Tissue Bank (UK NHS Health Research Authority, 15/NW/0932). This study (METR-GT: The Manchester Eye Tissue Repository Genome-Transcriptome Project, Ref# 15/NW/0932_16, PI=Jamie Ellingford) was granted approval by the Manchester Eye Tissue Repository ethical committee.

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All data produced in the present study are contained in the manuscript or available upon reasonable request to the authors