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

Citation

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, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control, Diabetes, 68, (2) pp. 441-456. ISSN 0012-1797 (2018) [Refereed Article]

Copyright Statement

2019 by the American Diabetes Association.

DOI: doi:10.2337/db18-0567

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 < 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.

Item Details

Item Type:Refereed Article
Keywords:genome, diabetic retinopathy, diabetes, glycemic control
Research Division:Medical and Health Sciences
Research Group:Ophthalmology and Optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Hearing, Vision, Speech and Their Disorders
UTAS Author:Burdon, KP (Professor Kathryn Burdon)
ID Code:130254
Year Published:2018
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-01-17
Last Modified:2019-03-22
Downloads:0

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