We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association to diabetic retinopathy in a genome-wide association study meta-analysis. Expression Quantitative Trait Loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified FLCN as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs to diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.
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Andrew D Skol
Department of Pathology and Laboratory Medicine, Ann and Robert H Lurie Children's Hospital of Chicago,, Chicago, United States
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The authors declare that no competing interests exist.
Segun C Jung
Research and Development, NeoGenomics Laboratories, Aliso Viejo, United States
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Ana Marija Sokovic
Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
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Siquan Chen
Cellular Screening Center, The University of Chicago, Chicago, United States
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Sarah Fazal
Cellular Screening Center, The University of Chicago, Chicago, United States
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Olukayode Sosina
Department of Biostatistics, Johns Hopkins University, Baltimore, United States
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Poulami P Borkar
Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
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Amy Lin
Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
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Maria Sverdlov
Research Histology and Tissue Imaging Core, University Of Illinois at Chicago, Chicago, United States
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Dingcai Cao
Ophthalmology and Visual Sciences, University Of Illinois at Chicago, Chicago, United States
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The authors declare that no competing interests exist.
Anand Swaroop
National Eye Institute, National Institutes of Health, Bethesda, United States
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