Unveiling the Genetic Landscape of Retinal Age Gap: Insights from a Genome-Wide Association Study

Abstract

Purpose : Retinal Age Gap (RAG), the discordance between chronological age and predicted retinal age based on retinal images, has emerged as a valuable predictor of age-related diseases. However, the full exploration of the biological implications and molecular mechanisms underlying RAG remains incomplete, limiting causal inference and targeted interventions for the aging process. This study aimed to conduct a comprehensive genome-wide association analysis (GWAS) on RAG, unveiling the biological inferences associated with accelerated retinal aging.

Methods : Our investigation commenced with a discovery GWAS on RAG, utilizing the extensive UK Biobank cohort (31,271 participants), with subsequent replication in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort (8,034 participants). To enhance the robustness of our findings, we employed Multi-trait Genome-Wide Association Analysis (MTAG) to integrate results from both cohorts. Post-GWAS analysis was conducted and further pleiotropy analysis was carried out to investigate genes contributing to diverse biological ages. Mendelian Randomization (MR) analysis was conducted to pinpoint causal factors related to RAG.

Results : Genetic correlation analysis revealed a robust correlation coefficient of 0.67 (P=0.021) between RAGs predicted from the UK Biobank and GoDARTs cohorts. MTAG identified 13 RAG loci, potentially influencing retinal vessel density and other aging processes. The SNP-wide heritability (h2) of RAG was estimated at 0.15. Gene-based enrichment analysis highlighted 9 prioritized genes. Pleiotropy analysis demonstrated that 8 RAG genes were shared with 'abdominal age,' 'lungs age,' 'biochemistry age,' or 'blood cells age.' Mendelian Randomization exposed associations between RAG and glycated hemoglobin, inflammation hemocytes, and anemia, suggesting potential contributors to accelerated retinal aging.

Conclusions : Our study sheds light on the genetic landscape of RAG, providing insights into the molecular mechanisms associated with retinal aging. The identified loci and associations offer avenues for causal inference of the aging process and present potential pharmaceutical intervention targets for future treatments.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.