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

Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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
JournalDiabetes
Volume68
Issue number2
DOIs
Publication statusPublished - 01-02-2019

Fingerprint

Genome-Wide Association Study
Diabetic Retinopathy
Gene Regulatory Networks
Hispanic Americans
African Americans
Introns
Meta-Analysis
Alleles
Genome
Inflammation
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Family Investigation of Nephropathy and Diabetes-Eye Research Group, & DCCT/EDIC Research Group (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
Family Investigation of Nephropathy and Diabetes-Eye Research Group ; DCCT/EDIC Research Group. / Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control. In: Diabetes. 2019 ; Vol. 68, No. 2. pp. 441-456.
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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 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.",
author = "{Family Investigation of Nephropathy and Diabetes-Eye Research Group} and {DCCT/EDIC Research Group} and Samuela Pollack and Igo, {Robert P.} and Jensen, {Richard A.} and Mark Christiansen and Xiaohui Li and Cheng, {Ching Yu} and Ng, {Maggie C.Y.} and Smith, {Albert V.} and Rossin, {Elizabeth J.} and Segr{\`e}, {Ayellet V.} and Samaneh Davoudi and Tan, {Gavin S.} and Chen, {Yii Der Ida} and Kuo, {Jane Z.} and Dimitrov, {Latchezar M.} and Stanwyck, {Lynn K.} and Weihua Meng and Hosseini, {S. Mohsen} and Minako Imamura and Darryl Nousome and Jihye Kim and Yang Hai and Yucheng Jia and Jeeyun Ahn and Aaron Leong and Kaanan Shah and Park, {Kyu Hyung} and Xiuqing Guo and Eli Ipp and Taylor, {Kent D.} and Adler, {Sharon G.} and Sedor, {John R.} and Freedman, {Barry I.} and Lee, {I. Te} and Sheu, {Wayne H.H.} and Michiaki Kubo and Atsushi Takahashi and Samy Hadjadj and Michel Marre and Tregouet, {David Alexandre} and Roberta Mckean-Cowdin and Rohit Varma and McCarthy, {Mark I.} and Leif Groop and Emma Ahlqvist and Valeriya Lyssenko and Elisabet Agardh and Andrew Morris and Doney, {Alex S.F.} and Colhoun, {Helen M.}",
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Family Investigation of Nephropathy and Diabetes-Eye Research Group & DCCT/EDIC Research Group 2019, 'Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control', Diabetes, vol. 68, no. 2, pp. 441-456. https://doi.org/10.2337/db18-0567

Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control. / Family Investigation of Nephropathy and Diabetes-Eye Research Group; DCCT/EDIC Research Group.

In: Diabetes, Vol. 68, No. 2, 01.02.2019, p. 441-456.

Research output: Contribution to journalArticle

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AU - Igo, Robert P.

AU - Jensen, Richard A.

AU - Christiansen, Mark

AU - Li, Xiaohui

AU - Cheng, Ching Yu

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AU - Rossin, Elizabeth J.

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AU - Davoudi, Samaneh

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AU - Chen, Yii Der Ida

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AU - Meng, Weihua

AU - Hosseini, S. Mohsen

AU - Imamura, Minako

AU - Nousome, Darryl

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AU - Hai, Yang

AU - Jia, Yucheng

AU - Ahn, Jeeyun

AU - Leong, Aaron

AU - Shah, Kaanan

AU - Park, Kyu Hyung

AU - Guo, Xiuqing

AU - Ipp, Eli

AU - Taylor, Kent D.

AU - Adler, Sharon G.

AU - Sedor, John R.

AU - Freedman, Barry I.

AU - Lee, I. Te

AU - Sheu, Wayne H.H.

AU - Kubo, Michiaki

AU - Takahashi, Atsushi

AU - Hadjadj, Samy

AU - Marre, Michel

AU - Tregouet, David Alexandre

AU - Mckean-Cowdin, Roberta

AU - Varma, Rohit

AU - McCarthy, Mark I.

AU - Groop, Leif

AU - Ahlqvist, Emma

AU - Lyssenko, Valeriya

AU - Agardh, Elisabet

AU - Morris, Andrew

AU - Doney, Alex S.F.

AU - Colhoun, Helen M.

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N2 - 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.

AB - 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.

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Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group. Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control. Diabetes. 2019 Feb 1;68(2):441-456. https://doi.org/10.2337/db18-0567