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

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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Abstract

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
Copyright Information:

© 2019 by the American Diabetes Association.

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