Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

, Samuela Pollack, Robert P. Igo, Richard A. Jensen, Mark Christiansen, Xiaohui Li, Ching-Yu Cheng, Maggie C. Y. Ng, Albert V. Smith, Elizabeth J. Rossin, Ayellet V. Segrè, Samaneh Davoudi, Gavin S. Tan, Yii-Der Ida Chen, Jane Z. Kuo, Latchezar M. Dimitrov, Lynn K. Stanwyck, Weihua Meng, S. Mohsen Hosseini, Minako ImamuraDarryl Nousome, Jihye Kim, Yang Hai, Yucheng Jia, Jeeyun Ahn, Aaron Leong, Kaanan Shah, Kyu Hyung Park, Xiuqing Guo, Eli Ipp, Kent D. Taylor, Sharon G. Adler, John R. Sedor, Barry I. Freedman, I-Te Lee, Wayne H-H Sheu, Michiaki Kubo, Atsushi Takahashi, Samy Hadjadj, Michel Marre, David-Alexandre Tregouet, Roberta Mckean-Cowdin, Rohit Varma, Mark I. McCarthy, Leif Groop, Emma Ahlqvist, Andrew Morris, Alexander Doney, Helen M. Colhoun, Paul Mitchell, Andrew D. Paterson, Colin Palmer, Alkes Price, Luca Sobrin

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Abstract

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 3 10 2 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 3 10 29 ), 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.

Original languageEnglish
Pages (from-to)441-456
Number of pages16
JournalDiabetes
Volume68
Issue number2
Early online date28 Nov 2018
DOIs
Publication statusPublished - 21 Jan 2019

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    , Pollack, S., Igo, R. P., Jensen, R. A., Christiansen, M., Li, X., Cheng, C-Y., Ng, M. C. Y., Smith, A. V., Rossin, E. J., Segrè, A. V., Davoudi, S., Tan, G. S., Ida Chen, Y-D., Kuo, J. Z., Dimitrov, L. M., Stanwyck, L. K., Meng, W., Hosseini, S. M., ... Sobrin, L. (2019). Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes, 68(2), 441-456. https://doi.org/10.2337/db18-0567