Genome-Wide Association Studies for Predisposition to Severe Diabetic Retinopathy Reveal Novel Susceptibility Loci

Abstract

Purpose: : To identify those genes and molecular networks that play a role in the pathogenesis of diabetic retinopathy complications. The genome-wide association study (GWAS) is a powerful tool to identify genetic variation affecting predisposition to common, complex diseases as they allow for a systematic survey of the entire genome without a priori knowledge of potential susceptibility alleles.

Methods: : We performed two independent GWAS’s and validated our findings in a third distinct cohort. The Genetics of Kidney in Diabetes (GoKinD) data set has phenotypic information from 1900 individuals with type 1 diabetes, who self-reported laser treatment for severe retinopathy. The cohort from the Epidemiology of Diabetes Intervention and Control Trial (EDIC) has 1441 subjects classified according to Early Treatment Diabetes Retinopathy Study (ETDRS) scores. The Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR) cohort is composed of 505 individuals with type 1 diabetes followed over a twenty-fiver year period whose retinopathy was defined by a modified ETDRS retinopathy severity score after grading of retinal photographs of 7 steroscopic 30° standard fields. Each study participant in GoKinD was genotyped using the Affymetrix SNP Array 5.0. In EDIC the Illumina platform was used for which 550K SNPs were available. Quality control steps insured sample integrity, identified highly related samples, and excluded population stratification. Allelic association tests were performed using PLINK. The top SNPs from the analysis using statistical, bioinformatic, and biologic criteria were validated in the WESDR cohort on the Illumina Golden Gate custom 1536 SNP bead array.

Results: : The most significant SNPs associated with the severe diabetic retinopathy phenotype demonstrated a p-value of 10-7 in the GWASs. In all there were 65 SNPs with a p-value of less than 10-4 in GoKinD. When evaluated in the EDIC cohort 23 of these 65 SNPs showed a p-value <0.01. When these 23 SNPs were evaluated in the WESDR cohort 2 SNPs demonstrated a p-value <0.05.

Conclusions: : GWA is a powerful approach to identify genetic loci that predispose to common, complex diseases. Using this technique we identified novel genetic loci that predispose to the retinal complications of diabetes.

Keywords: diabetic retinopathy • genetics • retinal neovascularization