In 223,051 UK Biobank men, mosaic loss of chromosome Y (LOY) in blood independently predicted incident age-related macular degeneration, with proteomic, single-cell, and mediation analyses supporting a somatic mutation–monocyte/macrophage–retinal axis.
LOY independently predicted increased risk of incident age-related macular degeneration (AMD) in men in the UK Biobank.
Restricted cubic spline analysis identified a risk escalation threshold for LOY at a median log R ratio of -0.17.
Plasma proteomics identified 41 prioritized proteins with divergent nonlinear trajectories over a 15-year preclinical window before diagnosis.
CD16+ circulating monocytes and resident macrophages showed the highest LOY frequencies in single-cell datasets of peripheral blood and choroidal tissue.
Y-deficient myeloid cells displayed a pro-inflammatory phenotype with cell-type-specific upregulation of IFI30 and CKB.
Peripheral monocyte counts significantly mediated the association between LOY and degenerative risk.
A LightGBM machine learning model using prioritized proteomic signatures predicted 5-year incident risk with an AUC of 0.734.
The authors conclude LOY defines a somatic mutation–immune–retinal axis and may be an upstream driver of site-specific organ degeneration.
This study looked at a common age-related change in men's blood cells: the loss of the Y chromosome in some cells (called LOY). Using data from more than 223,000 men in the UK Biobank, the researchers found that men with more LOY had a higher risk of later developing age-related macular degeneration, a leading cause of vision loss. The analysis also identified a level of LOY above which risk appeared to rise more sharply. Note that the hazard ratio printed in the abstract (0.611) is below 1, which would normally suggest lower risk, so the exact direction of the number is unclear from the abstract alone. The team also examined blood proteins measured years before diagnosis and found 41 proteins whose levels changed in distinct patterns up to 15 years ahead. One of them, MMP12, which breaks down elastin, began to differ about 12 years before diagnosis. Single-cell data showed that immune cells such as certain monocytes and macrophages, including those in the eye's choroid layer, most often lacked the Y chromosome and showed inflammatory features. Monocyte counts in the blood statistically explained part of the link between LOY and disease. This research suggests that LOY may be tied to eye disease through inflammation-related immune cells, and that blood protein patterns could help flag people at risk. A machine learning model built from these proteins predicted five-year risk with moderate accuracy (AUC 0.734). The study is observational and in men only, so it cannot by itself prove LOY causes eye disease, and the predictive model is not a diagnostic tool.
Chen T, Xiang Z, Zhang Z, Sun B, Ding X, Wang L, et al.. (2026). Systemic Loss of Chromosome Y Associates With Age-Related Ophthalmic Diseases in Middle-Aged Men: A Longitudinal Multi-Omic Study.. Aging cell. https://doi.org/10.1111/acel.70775