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

Publication ,  Journal Article
Pollack, S; Igo, RP; Jensen, RA; Christiansen, M; Li, X; Cheng, C-Y; Ng, MCY; Smith, AV; Rossin, EJ; Segrè, AV; Davoudi, S; Tan, GS; Kuo, JZ ...
Published in: Diabetes
February 2019

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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Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

February 2019

Volume

68

Issue

2

Start / End Page

441 / 456

Location

United States

Related Subject Headings

  • Protein Binding
  • Polymorphism, Single Nucleotide
  • Meta-Analysis as Topic
  • Humans
  • Glycated Hemoglobin
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Endocrinology & Metabolism
  • Diabetic Retinopathy
 

Citation

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ICMJE
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Pollack, S., Igo, R. P., Jensen, R. A., Christiansen, M., Li, X., Cheng, C.-Y., … 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
Pollack, Samuela, Robert P. Igo, Richard A. Jensen, Mark Christiansen, Xiaohui Li, Ching-Yu Cheng, Maggie C. Y. Ng, et al. “Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.Diabetes 68, no. 2 (February 2019): 441–56. https://doi.org/10.2337/db18-0567.
Pollack S, Igo RP, Jensen RA, Christiansen M, Li X, Cheng C-Y, et al. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes. 2019 Feb;68(2):441–56.
Pollack, Samuela, et al. “Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.Diabetes, vol. 68, no. 2, Feb. 2019, pp. 441–56. Pubmed, doi:10.2337/db18-0567.
Pollack S, Igo RP, Jensen RA, Christiansen M, Li X, Cheng C-Y, Ng MCY, Smith AV, Rossin EJ, Segrè AV, Davoudi S, Tan GS, Chen Y-DI, Kuo JZ, Dimitrov LM, Stanwyck LK, Meng W, Hosseini SM, Imamura M, Nousome D, Kim J, Hai Y, Jia Y, Ahn J, Leong A, Shah K, Park KH, Guo X, Ipp E, Taylor KD, Adler SG, Sedor JR, Freedman BI, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Lee I-T, Sheu WH-H, Kubo M, Takahashi A, Hadjadj S, Marre M, Tregouet D-A, Mckean-Cowdin R, Varma R, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Morris A, Doney ASF, Colhoun HM, Toppila I, Sandholm N, Groop P-H, Maeda S, Hanis CL, Penman A, Chen CJ, Hancock H, Mitchell P, Craig JE, Chew EY, Paterson AD, Grassi MA, Palmer C, Bowden DW, Yaspan BL, Siscovick D, Cotch MF, Wang JJ, Burdon KP, Wong TY, Klein BEK, Klein R, Rotter JI, Iyengar SK, Price AL, Sobrin L. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes. 2019 Feb;68(2):441–456.

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

February 2019

Volume

68

Issue

2

Start / End Page

441 / 456

Location

United States

Related Subject Headings

  • Protein Binding
  • Polymorphism, Single Nucleotide
  • Meta-Analysis as Topic
  • Humans
  • Glycated Hemoglobin
  • Genotype
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
  • Endocrinology & Metabolism
  • Diabetic Retinopathy