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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 with 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 folliculin ( 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 with 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.

Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes