Genetic drivers of pancreatic islet function

Nearly all gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets, and identified 18,775 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci where numerous transcripts co-map. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and show that these modules enrich for physiological pathways that also map to distinct loci. We identified and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and anot...