130254 - Multiethnic genome-wide association study of diabetic retinopathy.pdf (2.49 MB)Download file
Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control
journal contributionposted on 2023-05-19, 23:57 authored by Pollack, S, Igo Jr, RP, Jensen, RA, Christiansen, M, Li, X, Cheng, CY, Ng, MCY, Smith, AV, Rossin, EJ, Segre, 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, 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, Kathryn BurdonKathryn Burdon, 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 (GWAS). 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 X 10-5 were investigated in replication cohorts that included 18,545 Europeans, 16,453 Asians and 2,710 Hispanics. 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 x 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 (PDR) 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.
Department/SchoolMenzies Institute for Medical Research
PublisherAmer Diabetes Assoc
Place of publication1701 N Beauregard St, Alexandria, USA, Va, 22311-1717
Rights statementCopyright 2019 by the American Diabetes Association.