Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes
Andrew D Skol,
Segun C Jung,
Ana Marija Sokovic,
Siquan Chen,
Sarah Fazal,
Olukayode Sosina,
Poulami P Borkar,
Amy Lin,
Maria Sverdlov,
Dingcai Cao,
Anand Swaroop,
Ionut Bebu,
DCCT/EDIC Study group,
Barbara E Stranger,
Michael A Grassi
Affiliations
Andrew D Skol
Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, United States
Segun C Jung
Research and Development, NeoGenomics Laboratories, Aliso Viejo, United States
Ana Marija Sokovic
University of Illinois at Chicago, Chicago, United States
Siquan Chen
Cellular Screening Center, Office of Shared Research Facilities, The University of Chicago, Chicago, United States
Sarah Fazal
Cellular Screening Center, Office of Shared Research Facilities, The University of Chicago, Chicago, United States
Olukayode Sosina
Department of Biostatistics, Johns Hopkins University, Baltimore, United States; National Eye Institute, National Institutes of Health (NIH), Bethesda, United States
Poulami P Borkar
University of Illinois at Chicago, Chicago, United States
Amy Lin
University of Illinois at Chicago, Chicago, United States
Maria Sverdlov
University of Illinois at Chicago, Chicago, United States
Dingcai Cao
University of Illinois at Chicago, Chicago, United States
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.
