Title: Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.
Authors: Pollack, Samuela; Igo Jr, Robert P; Jensen, Richard A; Christiansen, Mark; Li, Xiaohui; Cheng, Ching-Yu; Ng, Maggie C Y; 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 S F; 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 E K; Klein, Ronald; Rotter, Jerome I; Iyengar, Sudha K; Price, Alkes L; Sobrin, Lucia
Published In Diabetes, (2019 02)
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.
PubMed ID: 30487263
MeSH Terms: Blood Glucose/metabolism; Diabetes Mellitus, Type 2/genetics*; Diabetes Mellitus, Type 2/metabolism; Diabetic Retinopathy; Genetic Predisposition to Disease; Genome-Wide Association Study/methods*; Genotype; Glycated Hemoglobin A/metabolism; Humans; Meta-Analysis as Topic; Polymorphism, Single Nucleotide/genetics; Protein Binding