Shared Genetic Architectures and Causal Associations Between Diabetic Retinopathy Progression and Frailty-Related...

Background/Objectives: Observational studies have reported comorbidity between diabetic retinopathy (DR) and physical frailty, but their genetic interplay remains incompletely understood. This study evaluated shared genetic architecture and potential causal relationships between DR severity and frailty-related phenotypes (FRPs). Methods: GWAS summary statistics were analyzed for four DR phenotypes (broad DR, background DR [BDR], severe non-proliferative DR, and proliferative DR [PDR]) and six FRPs, including frailty index (FI), appendicular lean mass, handgrip strength (HGS), and walking pace (UWP). Global and local genetic correlations were estimated using LDSC, HDL, and LAVA. Causality was assessed using bidirectional Mendelian randomization (MR) and latent causal variable (LCV) analyses. Biological mechanisms were investigated using partitioned heritability, cross-trait meta-analysis, Bayesian colocalization, tissue and cell enrichment, prioritization (MAGMA/TWAS), and 3D chromatin annotation. Results: BDR and PDR showed positive genetic correlations with FI and negative correlations with UWP. Local genetic correlation analyses identified 82 significant regions, including signals on chromosome 6. MR supported a directional effect in which genetic liability to DR was associated with higher FI and lower HGS, with no evidence of reverse causation. LCV indicated partial genetic causality within a shared polygenic architecture. Cross-trait meta-analysis and colocalization highlighted the MHC region, prioritizing C2, AIF1, NOTCH4, and EHMT2. Additional non-MHC loci included the BCL2L15 gene cluster and TERF1. Conclusions: DR and frailty share genetic determinants involving neurovascular, metabolic, and immune-inflammatory pathways, supporting an association between DR liability and frailty-related decline. Future longitudinal and functional studies are needed to validate these findings and assess candidate pleiotropic genes.