Systemic Loss of Chromosome Y Associates With Age-Related Ophthalmic Diseases in Middle-Aged Men: A Longitudinal Multi-Omic Study

Maintaining health during global population aging represents a critical challenge, where mosaic loss of chromosome Y (LOY) in the hematopoietic system surfaces as a prevalent somatic mutation in aging men. However, its longitudinal impact on sensory organ degeneration remains insufficiently characterized. Analyzing 223,051 male participants from the UK Biobank, we demonstrated that LOY uniquely and independently predicted an increased risk of incident age-related macular degeneration (AMD) (Hazard Ratio = 0.611, 95% Confidence Interval: 0.397-0.942). Restricted cubic splines identified a critical risk escalation threshold at -0.17 for median log R ratio. Over a 15-year preclinical window, Olink plasma proteomics identified 41 prioritized proteins demonstrating divergent nonlinear kinetic profiles leading up to clinical diagnosis; notably, the elastin-degrading matrix metalloproteinase-12 deviated significantly 12 years prior to endpoint. Integrating single-cell RNA sequencing datasets of peripheral blood and choroidal tissues validated that CD16+ circulatory monocytes and resident macrophages exhibited peak LOY frequencies. Furthermore, Y-deficient myeloid cells manifested a pro-inflammatory phenotype with cell-type-specific upregulation of IFI30 and CKB, bridging single-cell transcriptional activation with systemic proteomic dysregulation. Causal mediation analysis confirmed that peripheral monocyte counts significantly mediated the LOY-associated degenerative risk. Utilizing these prioritized proteomic signatures, a LightGBM machine learning framework achieved robust predictive performance for 5-year incident risk (AUC = 0.734). Collectively, these findings establish a distinct somatic mutation-immune-retinal axis, positioning systemic clonal mosaicism not merely as a marker of biological senescence but as an upstream driver of site-specific organ degeneration, offering novel strategies for early risk stratification and precision intervention in aging-related diseases.