Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.
Pollack S., Igo RP., Jensen RA., Christiansen M., Li X., Cheng C-Y., Ng MCY., Smith AV., Rossin EJ., Segrè AV., Davoudi S., Tan GS., Chen Y-DI., Kuo JZ., Dimitrov LM., Stanwyck LK., Meng W., Hosseini SM., Imamura M., Nousome D., Kim J., Hai Y., Jia Y., Ahn J., Leong A., Shah K., Park KH., Guo X., Ipp E., Taylor KD., Adler SG., Sedor JR., Freedman BI., Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group None., Lee I-T., Sheu WH-H., Kubo M., Takahashi A., Hadjadj S., Marre M., Tregouet D-A., Mckean-Cowdin R., Varma R., McCarthy MI., Groop L., Ahlqvist E., Lyssenko V., Agardh E., Morris A., Doney ASF., Colhoun HM., Toppila I., Sandholm N., Groop P-H., Maeda S., Hanis CL., Penman A., Chen CJ., Hancock H., Mitchell P., Craig JE., Chew EY., Paterson AD., Grassi MA., Palmer C., Bowden DW., Yaspan BL., Siscovick D., Cotch MF., Wang JJ., Burdon KP., Wong TY., Klein BEK., Klein R., Rotter JI., Iyengar SK., Price AL., Sobrin L.
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.