Ka Zhang

Diabetic retinopathy (DR) is a leading cause of vision loss, yet its systemic proteomic mediators remain largely elusive. This study aimed to identify causal plasma proteins, map their cell-type-specific localization in the retina, and experimentally validate their expression under disease-relevant stress. We conducted a proteome-wide association study (PWAS) integrating UK Biobank plasma pQTL data (N = 53,022) with DR GWAS summary statistics. Causal relationships were inferred utilizing summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Prioritized candidates were mapped to the Human and Mouse Retina Cell Atlases via single-nucleus RNA sequencing (snRNA-seq). Finally, to substantiate the computational findings, in vitro validation of COL4A1 was performed in ARPE-19 cells cultured under hyperglycemic conditions utilizing quantitative real-time PCR (qPCR) and transcriptomic dataset re-analysis. The PWAS identified 26 proteins significantly associated with DR. Subsequent causal inference prioritized 12 high-confidence candidates, including GSTT2B, COL4A1, PAM, and GALNT3. Notably, GSTT2B emerged as a Tier-1 protective causal protein (Z = −3.609; P_SMR = 1.22 × 10⁻⁴). snRNA-seq mapping revealed that GSTT2B is robustly expressed in Müller glia and the retinal pigment epithelium (RPE), whereas COL4A1 is prominently enriched in vascular compartments. These specific expression signatures exhibited partial conservation across species with notable cell-type specific variations. Crucially, in vitro validation confirmed that COL4A1 mRNA expression is significantly upregulated under high-glucose stress. Furthermore, druggability analysis highlighted actionable targets, identifying GSTT2B as a highly probable causal mediator and COL4A1 as a prioritized candidate for structural intervention. This study provides robust genetic, single-cell, and experimental evidence implicating specific plasma proteins in DR pathogenesis. The identification of GSTT2B-mediated protective pathways and the hyperglycemia-induced upregulation of COL4A1 offer a high-resolution molecular atlas to guide drug repositioning and precision therapeutic strategies.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm’s canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics.