A Proteomic Profile of the Ocular Phenome: Systemic Signatures, Predictive Value, and Causal Insights Across 131 Ocular Diseases and Traits

Vision loss remains one of the most pervasive and preventable global health burdens, yet ophthalmology has yet to fully benefit from molecular precision medicine. Unlike oncology and cardiometabolic diseases, the early detection and subtyping of eye disorders are hindered by limited access to intraocular tissues and a prevailing belief that the blood-ocular barrier precludes systemic biomarker utility. To systematically evaluate the relevance of the plasma proteome to ocular phenotypes, we profiled 2,920 circulating proteins in 53,016 UK Biobank participants across 80 clinically defined eye diseases and 51 quantitative ocular traits. We integrated association analyses, protein-based prediction models, Mendelian randomization, and unsupervised clustering to uncover predictive, causal, and mechanistic insights. We identified >2,700 significant protein-disease and >3,100 protein-trait associations, revealing widespread links between systemic proteins and intraocular features--particularly in diabetic retinopathy, intraocular pressure, and ISOS-RPE thickness. Plasma proteins such as GDF15, VSIG4, and PLAUR were consistently associated across phenotypes, implicating inflammation, vascular leakage, and complement signaling as convergent mechanisms. Proteome-based models outperformed clinical predictors in multiple conditions (e.g., AUC = 0.913 for diabetic retinopathy) and identified distinct risk gradients. Mendelian randomization supported causal roles for 144 proteins, including therapeutically actionable targets. Hierarchical clustering of 80 ocular phenotypes revealed six proteome-defined ocular modules, linking anatomically diverse traits through shared systemic biology and suggesting a new molecular taxonomy of eye health. This study provides the first comprehensive map of systemic protein signatures across the ocular phenome. By revealing biologically coherent associations across anatomically diverse ocular traits, our findings underscore the relevance of circulating proteins in reflecting both local ocular pathology and broader systemic physiology. These insights support the use of plasma proteomics for early detection, disease subtyping, and therapeutic exploration in ophthalmology, and position the eye as a clinically informative site of systemic biological signaling. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/25332495v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@2729adorg.highwire.dtl.DTLVardef@1213aaeorg.highwire.dtl.DTLVardef@93a753org.highwire.dtl.DTLVardef@1ce616b_HPS_FORMAT_FIGEXP M_FIG C_FIG