Mendelian randomization identifies folliculin expression as a mediator of diabetic retinopathy

The goal of the study was to identify genes whose aberrant expression can contribute to diabetic retinopathy. We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes (T1D) with and without retinopathy. Those genes exhibiting the largest difference in glucose response between individuals with diabetes with and without retinopathy were assessed for association to diabetic retinopathy utilizing genotype data from a genome-wide association study meta-analysis. All genetic variants associated with gene expression (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. We show that expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy compared to individuals with diabetes without retinopathy. Three large, independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs to diabetic retinopathy. Mendelian randomization further confirmed a direct positive effect of increased FLCN expression on retinopathy in individuals with diabetes. Together, our studies integrating genetic association and gene expression implicate FLCN as a disease gene for diabetic retinopathy.