Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

, Samuela Pollack, Robert P. Igo, 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 & 34 others 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, 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, Andrew Morris, Alexander Doney, Helen M. Colhoun, Paul Mitchell, Andrew D. Paterson, Colin Palmer, Alkes Price, Luca Sobrin

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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.

Original languageEnglish
Pages (from-to)441-456
Number of pages16
JournalDiabetes
Volume68
Issue number2
Early online date28 Nov 2018
DOIs
Publication statusPublished - 21 Jan 2019

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

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Pollack, Samuela ; Igo, 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. ; Ida Chen, Yii-Der ; 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. ; Lee, I-Te ; H-H Sheu, Wayne ; Kubo, Michiaki ; Takahashi, Atsushi ; Hadjadj, Samy ; Marre, Michel ; Tregouet, David-Alexandre ; Mckean-Cowdin, Roberta ; Varma, Rohit ; McCarthy, Mark I. ; Groop, Leif ; Ahlqvist, Emma ; Morris, Andrew ; Doney, Alexander ; Colhoun, Helen M. ; Mitchell, Paul ; Paterson, Andrew D. ; Palmer, Colin ; Price, Alkes ; Sobrin, Luca. / 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 = "Samuela Pollack and Igo, {Robert P.} and Jensen, {Richard A.} and Mark Christiansen and Xiaohui Li and Ching-Yu Cheng 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 {Ida Chen}, Yii-Der 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 I-Te Lee and {H-H Sheu}, Wayne and Michiaki Kubo and Atsushi Takahashi and Samy Hadjadj and Michel Marre and David-Alexandre Tregouet and Roberta Mckean-Cowdin and Rohit Varma and McCarthy, {Mark I.} and Leif Groop and Emma Ahlqvist and Andrew Morris and Alexander Doney and Colhoun, {Helen M.} and Paul Mitchell and Paterson, {Andrew D.} and Colin Palmer and Alkes Price and Luca Sobrin",
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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, Ida Chen, Y-D, 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, Lee, I-T, H-H Sheu, W, Kubo, M, Takahashi, A, Hadjadj, S, Marre, M, Tregouet, D-A, Mckean-Cowdin, R, Varma, R, McCarthy, MI, Groop, L, Ahlqvist, E, Morris, A, Doney, A, Colhoun, HM, Mitchell, P, Paterson, AD, Palmer, C & Price, A & Sobrin, L 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. /; Pollack, Samuela; Igo, 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.; Ida Chen, Yii-Der; 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.; Lee, I-Te; H-H Sheu, Wayne; Kubo, Michiaki; Takahashi, Atsushi; Hadjadj, Samy; Marre, Michel; Tregouet, David-Alexandre; Mckean-Cowdin, Roberta; Varma, Rohit; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Morris, Andrew; Doney, Alexander; Colhoun, Helen M.; Mitchell, Paul; Paterson, Andrew D.; Palmer, Colin; Price, Alkes (Lead / Corresponding author); Sobrin, Luca (Lead / Corresponding author).

In: Diabetes, Vol. 68, No. 2, 21.01.2019, p. 441-456.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

AU - Pollack, Samuela

AU - Igo, Robert P.

AU - Jensen, Richard A.

AU - Christiansen, Mark

AU - Li, Xiaohui

AU - Cheng, Ching-Yu

AU - Ng, Maggie C. Y.

AU - Smith, Albert V.

AU - Rossin, Elizabeth J.

AU - Segrè, Ayellet V.

AU - Davoudi, Samaneh

AU - Tan, Gavin S.

AU - Ida Chen, Yii-Der

AU - Kuo, Jane Z.

AU - Dimitrov, Latchezar M.

AU - Stanwyck, Lynn K.

AU - Meng, Weihua

AU - Hosseini, S. Mohsen

AU - Imamura, Minako

AU - Nousome, Darryl

AU - Kim, Jihye

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 - H-H Sheu, Wayne

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 - Morris, Andrew

AU - Doney, Alexander

AU - Colhoun, Helen M.

AU - Mitchell, Paul

AU - Paterson, Andrew D.

AU - Palmer, Colin

AU - Price, Alkes

AU - Sobrin, Luca

N1 - full list of funders on aam

PY - 2019/1/21

Y1 - 2019/1/21

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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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EP - 456

JO - Diabetes

JF - Diabetes

SN - 0012-1797

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