Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 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 P 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 (NVL) was associated with DR in European discovery cohorts (P = 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 (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Protein Binding
- Polymorphism, Single Nucleotide
- Meta-Analysis as Topic
- Humans
- Glycated Hemoglobin
- Genotype
- Genome-Wide Association Study
- Genetic Predisposition to Disease
- Endocrinology & Metabolism
- Diabetic Retinopathy
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Protein Binding
- Polymorphism, Single Nucleotide
- Meta-Analysis as Topic
- Humans
- Glycated Hemoglobin
- Genotype
- Genome-Wide Association Study
- Genetic Predisposition to Disease
- Endocrinology & Metabolism
- Diabetic Retinopathy