Purpose: Despite adequate glycemic control, a proportion of patients develop diabetic retinopathy (DR), suggesting the contribution of other mechanisms. To explore genetic associations with DR, we conducted a whole-exome sequencing (WES) study of DR using a dual-control design in individuals of European ancestry. Methods: Leveraging UK Biobank WES data, we implemented a dual-control design to identify candidate genes associated with DR, comparing cases with both diabetes controls and the general population. Rare variant associations were tested at gene-level using SAIGE-GENE+, and common variants were analyzed via PLINK2. Significant findings were assessed through the exclusion of self-reported cases, leave-one-variant-out (LOVO) analysis, time-to-event analysis, transcriptomics analysis, virtual knockout experiments, proteomics, and protein-protein interaction (PPI) analysis. Results: Exome-wide gene-based association analysis identified FRZB (frizzled-related protein) as a candidate gene potentially associated with DR in comparisons with diabetic controls (odds ratio OR = 1.09; 95% confidence interval CI, 1.04-1.15; P = 2.55 × 10-7). The observed association showed generally consistent patterns across several sensitivity analyses, including exclusion of self-reported cases, LOVO analyses, and Cox proportional hazards models. In addition, transcriptomic, proteomic, virtual knockout, and PPI analyses provided complementary exploratory evidence supporting a possible involvement of FRZB in DR-related biological processes. Additionally, single-variant analysis revealed two loci, FAM160A1 (4:151662612:C:G) and HK1 (10:69300854:A:G), associated with DR in the general population (OR = 1.82 and OR = 1.50, respectively). However, multiomics support for these signals was limited. Conclusions: This multilayered genetic study identified FRZB as a candidate gene potentially associated with DR. However, this finding should be interpreted cautiously, and further experimental studies and independent replication are needed to clarify the potential relevance of FRZB to DR.
Li et al. (2026) studied this question.