A genome-wide association study identifies EYA2 as a contributing gene for diabetic retinopathy in type 2 diabetes

Background: Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes. This study aims to identify the genetic variants associated with DR in type 2 diabetes (T2D) patients from the UK Biobank cohort (n = 16,988). Methods: We conducted a genome-wide association study (GWAS) of DR and integrated genomic results with multi-omics data to identify and prioritize susceptibility variants and genes. The findings are set to undergo validation in four replication cohorts. Results: Here we show that the lead SNP rs6066146 in EYA2 reaches genome-wide significance (p = 4.21×10⁻⁸) and is replicated in three independent cohorts. The SNP-based heritability for DR is estimated at 14.6% (standard deviation: 0.11). Colocalization analysis at the EYA2 locus suggests moderate colocalization (PP.H4 = 0.553) alongside distinct association signals for DR and T2D, and cis-Mendelian randomization (MR) within the EYA2 region provides gene-centric evidence that T2D exerts a significant causal effect on DR. Exploratory multivariable MR identifies proinsulin as a significant mediator of T2D on DR, which may partly account for the moderate evidence for colocalization. Tissue expression, chromatin interaction, and transcriptome-wide association analyses point to the spleen, while gene set analysis identifies B-cell pathways. Together, these convergent signals suggest that splenic B-cell abundance could serve as a predictive marker for DR risk. Conclusions: Our study demonstrates a genomic risk locus in gene EYA2 associated with DR in type 2 diabetes, which offers deeper insights into broader trait architecture on DR.