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


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.

SUBMITTER: Pollack S 

PROVIDER: S-EPMC6341299 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Pollack Samuela S   Igo Robert P RP   Jensen Richard A RA   Christiansen Mark M   Li Xiaohui X   Cheng Ching-Yu CY   Ng Maggie C Y MCY   Smith Albert V AV   Rossin Elizabeth J EJ   Segrè Ayellet V AV   Davoudi Samaneh S   Tan Gavin S GS   Chen Yii-Der Ida YI   Kuo Jane Z JZ   Dimitrov Latchezar M LM   Stanwyck Lynn K LK   Meng Weihua W   Hosseini S Mohsen SM   Hosseini S Mohsen SM   Imamura Minako M   Nousome Darryl D   Kim Jihye J   Hai Yang Y   Jia Yucheng Y   Ahn Jeeyun J   Leong Aaron A   Shah Kaanan K   Park Kyu Hyung KH   Guo Xiuqing X   Ipp Eli E   Taylor Kent D KD   Adler Sharon G SG   Sedor John R JR   Freedman Barry I BI   Lee I-Te IT   Sheu Wayne H-H WH   Kubo Michiaki M   Takahashi Atsushi A   Hadjadj Samy S   Marre Michel M   Tregouet David-Alexandre DA   Mckean-Cowdin Roberta R   Varma Rohit R   McCarthy Mark I MI   Groop Leif L   Ahlqvist Emma E   Lyssenko Valeriya V   Agardh Elisabet E   Morris Andrew A   Doney Alex S F ASF   Colhoun Helen M HM   Toppila Iiro I   Sandholm Niina N   Groop Per-Henrik PH   Maeda Shiro S   Hanis Craig L CL   Penman Alan A   Chen Ching J CJ   Hancock Heather H   Mitchell Paul P   Craig Jamie E JE   Chew Emily Y EY   Paterson Andrew D AD   Grassi Michael A MA   Palmer Colin C   Bowden Donald W DW   Yaspan Brian L BL   Siscovick David D   Cotch Mary Frances MF   Wang Jie Jin JJ   Burdon Kathryn P KP   Wong Tien Y TY   Klein Barbara E K BEK   Klein Ronald R   Rotter Jerome I JI   Iyengar Sudha K SK   Price Alkes L AL   Sobrin Lucia L  

Diabetes 20181128 2


To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (<i>n</i> = 3,246) and seven African American cohorts (<i>n</i> = 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 <i>P</i> value <1 × 10<sup>-5</sup> were investigated in replication cohor  ...[more]

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