Higher diabetes genetic load in proliferative diabetic retinopathy in South India: The South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) study

PURPOSE: To identify genomic risk factors for diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), in South Indians. METHODS: Phenotyping, including optical coherence tomography (OCT), of South Indians (n = 2538) with type 2 diabetes (T2D) was obtained. Genome-wide association studies (GWAS) were performed for DR, PDR, and DME with covariate adjustment. The results were replicated in two cohorts. T2D polygenic risk scores (PRS) were examined to determine if DR cases were enriched for T2D loci. RESULTS: A novel locus on chromosome 10 [rs11199996 (OR = 4.10, P = 2.88 × 10–8)] was associated with PDR, replicated in other cohorts, and is located near genes involved in retinal light transduction and growth hormone signaling. Several near genome-wide significant loci were identified, including rs76323047 in the glucokinase gene (GCK, P = 3.89 × 10–7), a glucose sensor; this risk variant displays higher frequency in Asian populations. T2D PRS showed consistent associations with DR, particularly PDR, suggesting that DR cases have a higher genetic load for T2D. CONCLUSION: This first DR GWAS in South Indians identified a significant association between a chromosome 10 variant and PDR. We also found notable associations of T2D PRS with DR.