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.
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, ; 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
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