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Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control


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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, Burdon, KP ORCID: 0000-0001-8217-1249, Wong, TY, Klein, BEK, Klein, R, Rotter, JI, Iyengar, SK, Price, AL and Sobrin, L 2018 , 'Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control' , Diabetes, vol. 68, no. 2 , pp. 441-456 , doi: 10.2337/db18-0567.

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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 -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.

Item Type: Article
Authors/Creators:Pollack, S and Igo Jr, RP and Jensen, RA and Christiansen, M and Li, X and Cheng, CY and Ng, MCY and Smith, AV and Rossin, EJ and Segre, AV and Davoudi, S and Tan, GS and Chen, Y-DI and Kuo, JZ and Dimitrov, LM and Stanwyck, LK and Meng, W and Hosseini, SM and Imamura, M and Nousome, D and Kim, J and Hai, Y and Jia, Y and Ahn, J and Leong, A and Shah, K and Park, KH and Guo, X and Ipp, E and Taylor, KD and Adler, SG and Sedor, JR and Freedman, BI and Lee, I-T and Sheu, WH-H and Kubo, M and Takahashi, A and Hadjadj, S and Marre, M and Tregouet, D-A and Mckean-Cowdin, R and Varma, R and McCarthy, MI and Groop, L and Ahlqvist, E and Lyssenko, V and Agardh, E and Morris, A and Doney, ASF and Colhoun, HM and Toppila, I and Sandholm, N and Groop, P-H and Maeda, S and Hanis, CL and Penman, A and Chen, CJ and Hancock, H and Mitchell, P and Craig, JE and Chew, EY and Paterson, AD and Grassi, MA and Palmer, C and Bowden, DW and Yaspan, BL and Siscovick, D and Cotch, MF and Wang, JJ and Burdon, KP and Wong, TY and Klein, BEK and Klein, R and Rotter, JI and Iyengar, SK and Price, AL and Sobrin, L
Keywords: genome, diabetic retinopathy, diabetes, glycemic control
Journal or Publication Title: Diabetes
Publisher: Amer Diabetes Assoc
ISSN: 0012-1797
DOI / ID Number: 10.2337/db18-0567
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Copyright 2019 by the American Diabetes Association.

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