Novel diabetes gene discovery through comprehensive characterization and integrative analysis of longitudinal gene expression changes

Type 2 diabetes is a complex, systemic disease affected by both genetic and environmental factors. Previous research has identified genetic variants associated with type 2 diabetes risk, however gene regulatory changes underlying progression to disease are still largely unknown. We investigated RNA expression changes that occur during diabetes progression using a two-stage approach. In our discovery stage, we compared changes in gene expression using two longitudinally collected blood samples from subjects who transitioned to type 2 diabetes between the time points against those who did not with a novel analytical network approach. Our network methodology identified 17 networks, one of which was significantly associated with transition status. This 822-gene network harbors many genes novel to the type 2 diabetes literature, but is also significantly enriched for genes previously associated with type 2 diabetes in GWAS. In the validation stage, we queried associations of genetically determined expression with diabetes-related traits in a large biobank with linked electronic health records. We observed a significant enrichment of genes in our identified network whose genetically determined expression is associated with type 2 diabetes and other metabolic traits and validated 31 gene-level associations that have never been reported by previous type 2 diabetes GWAS. Finally, we performed functional validation, demonstrating that the genes in this network are enriched in enhancers that operate in human pancreatic islet cells. We present an innovative and systematic approach that identified and validated key gene expression changes associated with type 2 diabetes transition status and demonstrated their translational relevance in a large clinical resource. Overall design: Longitudinal whole blood transcriptome profile of T2D progression