Pinpointing Novel Plasma and Brain Proteins for Common Ocular Diseases: A Comprehensive Cross-Omics Integration Analysis.

The pathogenesis of ocular diseases (ODs) remains unclear, although genome-wide association studies (GWAS) have identified numerous associated genetic risk loci. We integrated protein quantitative trait loci (pQTL) datasets and five large-scale GWAS summary statistics of ODs under a cutting-edge systematic analytic framework. Proteome-wide association studies (PWAS) identified plasma and brain proteins associated with ODs, and 11 plasma proteins were identified by Mendelian randomization (MR) and colocalization (COLOC) analyses as being potentially causally associated with ODs. Five of these proteins (protein-coding genes , , and for glaucoma, for age-related macular degeneration (AMD), and for diabetic retinopathy (DR)) are newly reported. Twenty brain-protein-OD pairs were identified by COLOC analysis. Eight pairs (protein-coding genes , , , and for senile cataract, and for AMD, for myopia, and for DR) are newly reported in this study. Phenotype-disease mapping analysis revealed 10 genes related to the eye/vision phenotype or ODs. Combined with a drug exploration analysis, we found that the drugs related to and have been used for the treatment of ODs, and another eight genes ( for senile cataract, and for AMD, for glaucoma, and for myopia, and for DR) are promising targets for pharmacological interventions. Our study highlights the role played by proteins in ODs, in which brain proteins were taken into account due to the deepening of eye-brain connection studies. The potential pathogenic proteins finally identified provide a more reliable reference range for subsequent medical studies.