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Genetics. 2018 May;209(1):335-356. doi: 10.1534/genetics.118.300864. Epub 2018 Mar 22.

Genetic Drivers of Pancreatic Islet Function.

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Department of Biochemistry, University of Wisconsin-Madison, Wisconsin 53706-1544.
The Jackson Laboratory, Bar Harbor, Maine 06409.
Maine School of Science and Mathematics, Limestone, Maine 06409.
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Wisconsin 53706-1544.
Department of Horticulture, University of Wisconsin-Madison, Wisconsin 53706-1544.
The Jackson Laboratory, Bar Harbor, Maine 06409
Department of Biochemistry, University of Wisconsin-Madison, Wisconsin 53706-1544


The majority of 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 high in fat (45% kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression QTL. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. 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 mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched-chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse and those found in human populations, and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.


T2D; eQTL; genome-wide association (GWA); mediation analysis; module-QTL; β-cell

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