Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes
eLife. 2020-11-09;:e59980.
- Abstract
- 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.
- Consortium data used in this publication
- Source files and code for all the figures and tables have been provided, except for drawings, flow- charts and histopathology findings. We have also included links and references where appropriate. Figure 3 source data 5 and 6 are available on Dryad at https://doi.org/10.5061/dryad.zkh18938j. Additional data files can be found here: microarray expression data at Gene Expression Omnibus (GEO) under accession code GSE146615 and diabetic retinopathy GWAS data at UKBB archive (https://biobank.ctsu.ox.ac.uk/crystal/docs.cgi?id=1).
- Datasets
- DSR673ZRD