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Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

  • Author(s): Pollack, Samuela
  • Igo, Robert P
  • Jensen, Richard A
  • Christiansen, Mark
  • Li, Xiaohui
  • Cheng, Ching-Yu
  • Ng, Maggie CY
  • Smith, Albert V
  • Rossin, Elizabeth J
  • Segrè, Ayellet V
  • Davoudi, Samaneh
  • Tan, Gavin S
  • Chen, Yii-Der Ida
  • Kuo, Jane Z
  • Dimitrov, Latchezar M
  • Stanwyck, Lynn K
  • Meng, Weihua
  • Hosseini, S Mohsen
  • Imamura, Minako
  • Nousome, Darryl
  • Kim, Jihye
  • Hai, Yang
  • Jia, Yucheng
  • Ahn, Jeeyun
  • Leong, Aaron
  • Shah, Kaanan
  • Park, Kyu Hyung
  • Guo, Xiuqing
  • Ipp, Eli
  • Taylor, Kent D
  • Adler, Sharon G
  • Sedor, John R
  • Freedman, Barry I
  • Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group
  • Lee, I-Te
  • Sheu, Wayne H-H
  • Kubo, Michiaki
  • Takahashi, Atsushi
  • Hadjadj, Samy
  • Marre, Michel
  • Tregouet, David-Alexandre
  • Mckean-Cowdin, Roberta
  • Varma, Rohit
  • McCarthy, Mark I
  • Groop, Leif
  • Ahlqvist, Emma
  • Lyssenko, Valeriya
  • Agardh, Elisabet
  • Morris, Andrew
  • Doney, Alex SF
  • Colhoun, Helen M
  • Toppila, Iiro
  • Sandholm, Niina
  • Groop, Per-Henrik
  • Maeda, Shiro
  • Hanis, Craig L
  • Penman, Alan
  • Chen, Ching J
  • Hancock, Heather
  • Mitchell, Paul
  • Craig, Jamie E
  • Chew, Emily Y
  • Paterson, Andrew D
  • Grassi, Michael A
  • Palmer, Colin
  • Bowden, Donald W
  • Yaspan, Brian L
  • Siscovick, David
  • Cotch, Mary Frances
  • Wang, Jie Jin
  • Burdon, Kathryn P
  • Wong, Tien Y
  • Klein, Barbara EK
  • Klein, Ronald
  • Rotter, Jerome I
  • Iyengar, Sudha K
  • Price, Alkes L
  • Sobrin, Lucia
  • et al.

Published Web Location

https://doi.org/10.2337/db18-0567
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 × 10-5 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 × 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 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.

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