Abstract
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.
Plain language summary
Diabetic retinopathy (DR) is an eye disease caused by diabetes that can lead to vision loss. We studied about 17,000 people with type 2 diabetes and compared the DNA of those with and without DR. A genome-wide association analysis is a method that scans the entire genome for markers associated with a specific condition. By scanning their entire genomes and combining this with other biological information, we found a strong risk signal at the EYA2 gene on chromosome 20 that impacts DR. This gene has also been linked to type 2 diabetes itself. Our findings suggest that EYA2 and its pathways could be promising targets for future treatments that might help protect against both diabetes and its retinal complications.
Data availability
The individual-level genotype and phenotype data used in this study are available from the UK Biobank under controlled access and can be obtained by approved researchers through application to the UK Biobank. The source data underlying the figures presented in this study are provided in the Supplementary Information. Specifically, the summary statistics data for the Manhattan plot in Fig. 2 is provided in Supplementary Data. The source data for Fig. 3A are in Supplementary Table 6. The source data for Fig. 3B are in Supplementary Table 7. The source data for Fig. 3C, D are in Supplementary Table 8. The source data for Fig. 4 are in Supplementary Table 9. The source data for Fig. 5 are in Supplementary Table 12. GoDARTS summary statistics used in this study were provided by Aravind L. Rajendrakumar from his PhD thesis and will be made available to qualified researchers upon reasonable request. Other summary statistics for Mendelian randomization are available in the IEU OpenGWAS database. The eQTL data used for the analyses described in this manuscript were obtained from the GTEx Portal on 05/10/2025. Should any data pertinent to this study need to be presented within this paper or its other files, the authors can provide such data upon reasonable request.
Code availability
Custom scripts used for data processing and analysis are available from the corresponding authors upon reasonable request.
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Acknowledgements
The authors gratefully thank all the participants and professionals contributing to the UKB, GoDARTS, FinnGen, and African American & European ancestry studies. This study adheres to all ethical guidelines and data protection protocols of the UK Biobank. The current study was conducted under the approved UK Biobank data application number 50604. This study was mainly funded by the Pioneer and Leading Goose R&D Program of Zhejiang Province 2023, with reference number 2023C04049, and the Ningbo International Collaboration Program 2023, with reference number 2023H025.
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T.C. drafted the paper and performed the GWAS analysis. Q.P. and Y.T. contributed to data formatting and correction. C.N., A.R., Y.Y., T.D., M.H., and C.P. provided comments on the paper. Y.S. and W.M. organized the project and provided comments.
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Communications Medicine thanks Shi Song Rong and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Cai, T., Pan, Q., Tao, Y. et al. A genome-wide association study identifies EYA2 as a contributing gene for diabetic retinopathy in type 2 diabetes. Commun Med (2026). https://doi.org/10.1038/s43856-026-01465-1
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DOI: https://doi.org/10.1038/s43856-026-01465-1