Abstract
Age-related macular degeneration (AMD), cataract, and glaucoma are leading causes of blindness worldwide. Previous genome-wide association studies (GWASs) have revealed a variety of susceptible loci associated with age-related ocular disorders, yet the genetic pleiotropy and causal genes across these diseases remain poorly understood. By leveraging large-scale genetic and observational data from ocular disease GWASs and UK Biobank (UKBB), we found significant pairwise genetic correlations and consistent epidemiological associations among these ocular disorders. Cross-disease meta-analysis uncovered seven pleiotropic loci, three of which were replicated in an additional cohort. Integration of variants in pleiotropic loci and multiple single-cell omics data identified that Müller cells and astrocytes were likely trait-related cell types underlying ocular comorbidity. In addition, we comprehensively integrated eye-specific gene expression quantitative loci (eQTLs), epigenomic profiling, and 3D genome data to prioritize causal pleiotropic genes. We found that pleiotropic genes were essential in nerve development and eye pigmentation, and targetable by aflibercept and pilocarpine for the treatment of AMD and glaucoma. These findings will not only facilitate the mechanistic research of ocular comorbidities but also benefit the therapeutic optimization of age-related ocular diseases.
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Data availability
The data repository of full GWAS summary statistics for this study is provided in Table S1. Ocular scRNA-seq and single-cell multiome data can be downloaded at https://www.ncbi.nlm.nih.gov/geo/. The loops of retinal H3K27ac HiChIP are available at https://www.biorxiv.org/content/10.1101/2022.03.09.483684v1.supplementary-material.
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This study was supported by the National Natural Science Foundation of China (Grant Numbers 82020108007, 81830026, 32070675) and National Key Research and Development Program of China (Grant Number 2021YFC2401404).
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HY and MJL conceived of the project. XY, HY, and YJ performed the analyses. HH, XK, and ML contributed to the data collection and processing. YZ, JW, and XF contributed to manuscript polishing and provided analysis suggestions. XY, MJL, and HY wrote the manuscript. The authors read and approved the final submission.
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Yao, X., Yang, H., Han, H. et al. Genome-wide analysis of genetic pleiotropy and causal genes across three age-related ocular disorders. Hum Genet 142, 507–522 (2023). https://doi.org/10.1007/s00439-023-02542-4
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DOI: https://doi.org/10.1007/s00439-023-02542-4