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Background: <p>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 (<i>n</i> = 16,988).</p> Methods: <p>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.</p> Results: <p>Here we show that the lead SNP rs6066146 in <i>EYA2</i> reaches genome-wide significance (<i>p</i> = 4.21×10<sup>−8</sup>) 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 <i>EYA2</i> locus suggests moderate colocalization (PP.H4 = 0.553) alongside distinct association signals for DR and T2D, and cis-Mendelian randomization (MR) within the <i>EYA2</i> 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.</p> Conclusions: <p>Our study demonstrates a genomic risk locus in gene <i>EYA2</i> associated with DR in type 2 diabetes, which offers deeper insights into broader trait architecture on DR.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Tengda Cai,
  • Qi Pan,
  • Yiwen Tao,
  • Charvi Nangia,
  • Aravind L. Rajendrakumar,
  • Yunyan Ye,
  • Tania Dottorini,
  • Mainul Haque,
  • Colin NA Palmer,
  • Yongqing Shao,
  • Weihua Meng

摘要

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.