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

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.

• Authors: Samuela Pollack, Robert P Igo Jr, 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 Imamura, Darryl 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, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, 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, Valeriya Lyssenko, Elisabet Agardh, Andrew Morris, Alex S F Doney, Helen M Colhoun, Iiro Toppila, Niina Sandholm, Per-Henrik Groop, Shiro Maeda, Craig L Hanis, Alan Penman, Ching J Chen, Heather Hancock, Paul Mitchell, Jamie E Craig, Emily Y Chew, Andrew D Paterson, Michael A Grassi, Colin Palmer, Donald W Bowden, Brian L Yaspan, David Siscovick, Mary Frances Cotch, Jie Jin Wang, Kathryn P Burdon, Tien Y Wong, Barbara E K Klein, Ronald Klein, Jerome I Rotter, Sudha K Iyengar, Alkes L Price, Lucia Sobrin
• Journal: Diabetes (Diabetes) Vol. 68 Issue 2 Pg. 441-456 (02 2019) ISSN: 1939-327X [Electronic] United States
• PMID: 30487263 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the American Diabetes Association.

Chemical References

• Blood Glucose
• Glycated Hemoglobin A

Topics

• Blood Glucose (metabolism)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Diabetic Retinopathy
• Genetic Predisposition to Disease
• Genome-Wide Association Study (methods)
• Genotype
• Glycated Hemoglobin (metabolism)
• Humans
• Meta-Analysis as Topic
• Polymorphism, Single Nucleotide (genetics)
• Protein Binding