Journal Article

436 Genetic clues to blurred vision: A multi-ancestry GWAS of diabetic macular edema

Kim, Jeewoo, Breeyear, Joseph H., Hellwege, Jacklyn N., Otieno, Christopher, Graham, Robert, Edwards, Todd L., Mozaffari, Sahar, Yaspan, Brian, Seagle, Hannah M.

2026

Overview

Objectives/Goals: Identify genetic variants associated with the development of diabetic retinopathy (DR) and its advanced complication, diabetic macular edema (DME). Despite DME being a leading cause of vision loss among people with diabetes, genetic findings have been limited by small sample size, underrepresentation of diverse populations, and poor study design. Methods/Study Population: Genome-wide association studies (GWAS) were conducted to identify genetic variants linked to DME. GWAS were conducted separately by ancestry (African, European, and Admixed American) in the Million Veteran Program and All of Us cohorts, adjusted for age, sex, BMI, diabetes duration, mean HbA1c, and 10 principal components. We then combined population groups to perform a multi-ancestry meta-analysis (Multi) using a software called METAL. Analyses included autosomes and chromosome X for DME versus DR controls (14,211 cases and 47,005 controls). Gene expression analyses were performed using S-PrediXcan across 49 tissues to identify genes whose predicted expression is associated with DME risk. APOL1 variant and haplotype analyses were conducted to assess ancestry-specific associations with DME and type 2 diabetes. Results/Anticipated Results: Genome-wide significant loci included G6PD (Multi and African), previously reported to influence diabetes diagnosis, and APOL1 (Multi and European), previously linked to kidney disease in African ancestry. Gene expression analyses revealed 32 significant gene–tissue pairs (Multi 18 and African 18), corresponding to 9 unique genes. In APOL1, E150K was strongly associated with DME in Europeans (OR=1.22, P=2.9×10 −8 ) and modestly in Africans (OR=1.18, P=5.3×10 −4 ). N264K also showed significant effects in Europeans (OR=1.42, P=9.8×10 −4 ) and weaker but consistent effects in Africans (OR=1.04, P=0.025). The high-risk G1/G2 haplotype demonstrated a modest association in African ancestry (OR=1.15, P=0.048). Discussion/Significance of Impact: This is the largest genetic study of DME, uncovering genetic risk factors that could potentially be driving risk, such as APOL1, a gene historically tied to kidney disease among individuals of African ancestry. Our results indicate its involvement may extend to diabetic complications more generally.

• Publisher: Cambridge University Press
• Subject: Diabetes / Diabetes mellitus (non-insulin dependent) / Edema / Gene expression / Genetic diversity / Genome-wide association studies / Genomes / Glucosephosphate dehydrogenase / Haplotypes / Health risk assessment / Kidney diseases / Population studies / Precision Medicine/Health / Retinopathy / Risk factors / Somatic chromosomes / Vision