Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (<i>n</i> = 3,246) and seven African American cohorts (<i>n</i> = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a <i>P</i> value <1 × 10^-5 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (<i>NVL</i>) was associated with DR in European discovery cohorts (<i>P</i> = 2.1 × 10^-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (<i>P</i> = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in <i>NVL,</i> as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.