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 language | English |
|---|---|
| Pages (from-to) | 441-456 |
| Number of pages | 16 |
| Journal | Diabetes |
| Volume | 68 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 01-02-2019 |
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All Science Journal Classification (ASJC) codes
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
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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 journal › Article
TY - JOUR
T1 - Multiethnic genome-wide association study of diabetic retinopathy using liability threshold modeling of duration of diabetes and glycemic control
AU - Family Investigation of Nephropathy and Diabetes-Eye Research Group
AU - DCCT/EDIC Research Group
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 - Chen, Yii Der Ida
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 - 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.
PY - 2019/2/1
Y1 - 2019/2/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85060253807&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060253807&partnerID=8YFLogxK
U2 - 10.2337/db18-0567
DO - 10.2337/db18-0567
M3 - Article
C2 - 30487263
AN - SCOPUS:85060253807
VL - 68
SP - 441
EP - 456
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 2
ER -