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

Samuela Pollack, 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, Latchezar M. Dimitrov, Lynn K. Stanwyck, Weihua Meng, S. Mohsen Hosseini, Minako Imamura, Darryl Nousome, Jihye Kim, Yang HaiYucheng Jia, Jeeyun Ahn, Aaron Leong, Kaanan Shah, Kyu Hyung Park, Eli Ipp, Kent D. Taylor, Sharon G. Adler, John R. Sedor, Barry I. Freedman, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Andrew Paterson

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


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
Issue number2
Publication statusPublished - 1 Feb 2019


  • diabetic retinopathy
  • genetic variants
  • multiethnic genome-wide association study


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