Data from: 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 another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, reflecting heterogeneity within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with clinical 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 genes and pathways linked to diabetes-associated clinical traits. Our analysis reveals a high degree of concordance between diabetes-associated loci in the mouse with those found in human populations, and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.几乎所有与2型糖尿病（type 2 diabetes）相关的基因位点（gene loci）均在胰岛功能中发挥作用。为评估胰岛基因表达在糖尿病病因学中的作用，我们采用西式饮食（Western diet）致敏遗传多样性小鼠种群，并对糖尿病相关表型开展全基因组关联定位（genome-wide association mapping）。我们定量检测了胰岛中的mRNA丰度，鉴定得到18775个表达数量性状位点（expression quantitative trait loci）。我们应用中介分析（mediation analysis），在多个转录本共定位的位点中筛选候选因果驱动基因。这些基因包括此前与单基因糖尿病（monogenic diabetes）相关的2个基因（PDX1和HNF4A），以及在人群中与糖尿病相关性状存在名义关联的3个基因（FAM83E、IL6ST和SAT2）。我们将转录本划分为基因模块，并证实这些模块富集于亦定位于不同位点的生理通路。我们鉴定并定位了富集于α细胞（α-cells）特异性转录本的模块，以及另一个富集于δ细胞（δ-cells）特异性转录本的模块。然而，并无任何模块富集于β细胞（β-cells）特异性转录本，这反映了β细胞群体内的异质性。一个富集于与支链氨基酸代谢（branched chain amino acid metabolism）相关转录本的模块，与反映胰岛素抵抗（insulin resistance）的临床性状相关性最强。尽管本研究中的小鼠未表现出显性糖尿病，但通过对饮食诱导应激下的胰岛基因表达进行分析，我们得以鉴定出与糖尿病相关临床性状存在关联的基因及通路。我们的分析揭示了小鼠中糖尿病相关位点与人群中发现的相关位点高度一致，并证实了小鼠模型可为人类全基因组关联定位中发现的名义关联提供佐证。