Genome-Wide Association Study to Identify Genetic Variants Associated With Diabetic Maculopathy.

Purpose: Diabetic maculopathy (including diabetic macular edema [DME]) is the leading cause of vision loss in people with diabetes. We aimed to identify the genetic determinants of diabetic maculopathy.

Methods: We conducted a genome-wide association study (GWAS) in two cohorts with a meta-analysis. The Australian cohort comprised 551 cases of DME and 599 controls recruited from the states of South Australia and Tasmania. The Scottish cohort comprised 1951 cases of diabetic maculopathy and 6541 controls from the Genetics of Diabetes Audit and Research in Tayside Scotland study (GoDARTS). Genotyping, imputation, and association analysis using logistic regression were conducted in each cohort, before combining summary statistics in a meta-analysis using the GWAMA package.

Results: A locus on chromosome 7 reached genome-wide significance in GoDARTS but showed the opposite direction of effect in the Australian cohort. The meta-analysis identified two suggestive associations (P < 5 × 10-6) for diabetic maculopathy risk with similar effect direction; one at chromosome 1 close to the RNU5E-1 gene and one at chromosome 13 upstream of the ERICH6B gene. The two loci were evaluated in silico for potential functional links to diabetic maculopathy. Both are located in regulatory regions and have annotations indicating regulatory functions. They are also expression quantitative trait locus (eQTLs) for genes plausibly involved in diabetic maculopathy pathogenesis, with links to folate metabolism and the regulation of VEGF.

Conclusions: The study suggests several promising SNPs and genes related to diabetic maculopathy risk. Despite being the largest genetic study of diabetic maculopathy to date, larger, homogeneous cohorts will be required to identify robust genetic risk loci for the disease.