Systemic Loss of Chromosome Y Associates With Age-Related Ophthalmic Diseases in Middle-Aged Men: A Longitudinal Multi-Omic Study.
6 affiliations
- 1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.
- 2NHC Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China.
- 3Shanghai Research Center of Ophthalmology and Optometry, Eye & ENT Hospital, Fudan University, Shanghai, China.
- 4Shanghai Engineering Research Center of Laser and Autostereoscopic 3D for Vision Care, Eye & ENT Hospital, Fudan University, Shanghai, China.
- 5Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University, Shanghai, China.
- 6Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
Abstract
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.
Related
- Age-related clonal hematopoiesis and mosaic sex chromosome loss define distinct systemic proteomic programs and disease vulnerabilities
- Development and validation of an AI-enhanced prediction model for 3-year visual decline in patients with diabetes using ophthalmic imaging: protocol for a real-world longitudinal cohort study
- Lipid and immune profiles in children with systemic juvenile idiopathic arthritis: a case-control study with paired longitudinal comparison of disease activity
- ECG-based longitudinal risk prediction across diseases and organ systems
- Association Between Frailty Index and New-Onset Stroke in Middle-Aged and Elderly Chinese Adults with Gastrointestinal or Liver Diseases: A Longitudinal Cohort Study
BibTeX
@article{chen2026systemic,
title = {{Systemic Loss of Chromosome Y Associates With Age-Related Ophthalmic Diseases in Middle-Aged Men: A Longitudinal Multi-Omic Study.}},
author = {Tianhao Chen and Zhaoyu Xiang and Zhe Zhang and Bingqing Sun and Xuan Ding and Liyin Wang and Yunqian Yao and Zhuotong Wu and Siyang Liu and Yuan Lei and Xingtao Zhou and Jing Zhao},
journal = {Aging cell},
year = {2026},
month = oct,
doi = {10.1111/acel.70775},
url = {https://europepmc.org/article/MED/42894102},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systemic Loss of Chromosome Y Associates With Age-Related Ophthalmic Diseases in Middle-Aged Men: A Longitudinal Multi-Omic Study.
AU - Tianhao Chen
AU - Zhaoyu Xiang
AU - Zhe Zhang
AU - Bingqing Sun
AU - Xuan Ding
AU - Liyin Wang
AU - Yunqian Yao
AU - Zhuotong Wu
AU - Siyang Liu
AU - Yuan Lei
AU - Xingtao Zhou
AU - Jing Zhao
PY - 2026
DA - 2026/10/01
JO - Aging cell
DO - 10.1111/acel.70775
UR - https://europepmc.org/article/MED/42894102
AB - 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.
SN - 1474-9718
SN - 1474-9726
ER -