Investigating the Shared Genetic Architecture of 3 Age-Related Ocular Disorders

Purpose

To explore the shared genetic architecture, causal relationships, and cell type–specific expression patterns of pleiotropic genes in age-related macular degeneration (AMD), cataract, and primary open-angle glaucoma (POAG), uncovering molecular mechanisms and informing targeted therapies.

Design

A genetic association study combined with cross-trait meta-analyses, Mendelian randomization analyses, and single-cell RNA sequencing (scRNA-seq) analysis.

Subjects

The data related to 3 age-related ocular diseases, including AMD, cataract, and POAG, were obtained from publicly available genome-wide association study (GWAS) databases.

Methods

We conducted a comprehensive genetic analysis utilizing GWAS summary statistics to examine genetic correlations among AMD, cataract, and POAG. Cross-trait meta-analyses were performed to identify shared risk loci. Mendelian randomization was employed to investigate potential causal relationships between these conditions. Additionally, we analyzed scRNA-seq data to examine the expression patterns of identified pleiotropic genes across different retinal cell types.

Main Outcome Measures

Identification of shared risk single nucleotide polymorphisms (SNPs) and pleiotropic loci. Causal relationships between AMD, cataract, and POAG. Cell type–specific expression patterns of pleiotropic genes in retinal cells.

Results

Our analysis revealed significant genetic correlations, with a negative correlation between AMD and POAG and a positive correlation between cataract and POAG. Cross-trait meta-analyses identified shared risk SNPs, with CDKN2B-AS1 emerging as a notable pleiotropic locus. Mendelian randomization analyses suggested causal relationships between AMD and cataract, as well as between POAG and AMD. Single-cell expression analysis demonstrated cell type–specific expression patterns of pleiotropic genes including ATXN2, HTRA1, SIX6, and THSD7A across retinal cells.

Conclusions

This study provides compelling evidence for shared genetic architecture and causal relationships among AMD, cataract, and POAG. The identification of specific pleiotropic genes and their expression patterns across retinal cell types offers new insights into the molecular mechanisms underlying these age-related ocular diseases, potentially informing the development of targeted therapeutic strategies.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.