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

To identify genomic risk factors for diabetic retinopathy (DR), proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME), in South Indians. 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. 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. 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. Established risk factors for diabetic retinopathy (DR) are poor glycemic control and longer duration of diabetes, but they do not fully explain the development and progression of DR. Most genetic studies based on DR have been focused on European and East Asian populations, with very limited work in South Indian cohorts, despite their higher disease burden. Established risk factors for diabetic retinopathy (DR) are poor glycemic control and longer duration of diabetes, but they do not fully explain the development and progression of DR. Most genetic studies based on DR have been focused on European and East Asian populations, with very limited work in South Indian cohorts, despite their higher disease burden. A novel locus on chromosome 10 located near genes involved in retinal light transduction was associated with proliferative diabetic retinopathy in this South Indian population. A near genome-wide significant locus was also identified in the glucokinase gene; the risk variant at this locus has a higher frequency in Asian populations. Type 2 diabetes polygenic risk scores showed consistent associations with DR, suggesting that DR cases have a higher genetic load for type 2 diabetes risk variants. A novel locus on chromosome 10 located near genes involved in retinal light transduction was associated with proliferative diabetic retinopathy in this South Indian population. A near genome-wide significant locus was also identified in the glucokinase gene; the risk variant at this locus has a higher frequency in Asian populations. Type 2 diabetes polygenic risk scores showed consistent associations with DR, suggesting that DR cases have a higher genetic load for type 2 diabetes risk variants.