Mendelian randomization study implicates inflammaging biomarkers in retinal vasculature, cardiovascular diseases, and longevity
With the increasing proportion of elderly individuals, understanding biological mechanisms of aging is critical. Retinal vascular complexity, measured as fractal dimension (<i>D</i><sub>f</sub>) from fundus photographs, has emerged as a vascular aging indicator. We conducted a genome-wide association study of <i>D</i><sub>f</sub> on 74,434 participants from the Canadian Longitudinal Study on Aging, Genetics of Diabetes Audit and Research in Tayside Scotland, and UK Biobank cohorts. We identified a novel locus near <i>DAAM1</i>. We found negative genetic correlations between <i>D</i><sub>f</sub> and cardiovascular disease, stroke, and inflammation but a positive correlation with life span. By combining the genetic determinants of 1159 circulating proteins from the Prospective Urban and Rural Epidemiological cohort with those of <i>D</i><sub>f</sub> using Mendelian randomization, we identified eight causal mediators, including MMP12 and IgG-Fc receptor IIb, which link higher inflammation to lower <i>D</i><sub>f</sub>, increased cardiovascular disease risk, and shorter life span. These results extend our understanding of the biological pathways underlying aging processes and inform targets to prevention and treatment.
Authors
- Marie Pigeyre (ORCID: https://orcid.org/0000-0003-2984-8366)
- Alex S. F. Doney (ORCID: https://orcid.org/0000-0002-6210-5620)
- Miguel O. Bernabéu (ORCID: https://orcid.org/0000-0002-6456-3756)
- Salim Yusuf (ORCID: https://orcid.org/0000-0003-4776-5601)
- Walter Nelson (ORCID: https://orcid.org/0000-0002-5216-7617)
- Jeremy Petch (ORCID: https://orcid.org/0000-0003-1614-1046)
- Hertzel C. Gerstein (ORCID: https://orcid.org/0000-0001-8072-2836)
- Nicolas Perrot (ORCID: https://orcid.org/0000-0002-2395-2333)
- Albert Tenesa (ORCID: https://orcid.org/0000-0003-4884-4475)
- Konrad Rawlik (ORCID: https://orcid.org/0000-0002-0010-370X)
- Emanuele Trucco (ORCID: https://orcid.org/0000-0002-5055-0794)
- Guillaume Paré (ORCID: https://orcid.org/0000-0002-6795-4760)
- Ana Villaplana-Velasco (ORCID: https://orcid.org/0000-0002-4759-178X)
- Muthu Rama Krishnan Mookiah (ORCID: https://orcid.org/0000-0001-6437-1482)
- Michael Chong (ORCID: https://orcid.org/0000-0002-0555-4622)
- Erola Pairo‐Castineira (ORCID: https://orcid.org/0000-0002-2423-3090)
- Yu Huang (ORCID: https://orcid.org/0000-0001-5355-0047)
Institutions
- Roslin Institute (GB)
- University of Dundee (GB)
- University of Toronto (CA)
- Population Health Research Institute (CA)
- Edinburgh College (GB)
- Centre for Inflammation Research (GB)
- Genomics (United Kingdom) (GB)
- Thrombosis and Atherosclerosis Research Institute (CA)
- Impact (CA)
- The Queen's Medical Research Institute (GB)
- Hamilton Health Sciences (CA)
- McMaster University (CA)
- University of Edinburgh (GB)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1126/sciadv.adu1985
- Citations
- 1
- Primary Topic
- Retinal Imaging and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 1.36
Funders
- British Heart Foundation
- Diabetes UK
- Fight for Sight UK
- Medical Research Council