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

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).

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.

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.

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.