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.

几乎所有已被证实与2型糖尿病（type 2 diabetes）相关的基因位点，均在胰岛功能中发挥作用。为探究胰岛基因表达在糖尿病病因学中的作用，我们以西式饮食（Western diet）处理遗传多样性小鼠群体，使其对糖尿病易感，并针对糖尿病相关表型开展全基因组关联定位（genome-wide association mapping）分析。我们对胰岛中的mRNA丰度进行定量检测，共鉴定得到18775个表达数量性状位点（expression quantitative trait loci, eQTL）。我们采用中介分析（mediation analysis），在多个转录本共定位的基因位点处筛选潜在的因果驱动基因，其中包含2个此前已被证实与单基因糖尿病（monogenic diabetes）相关的基因（PDX1与HNF4A），以及3个在人类中与糖尿病相关性状存在名义关联的基因（FAM83E、IL6ST与SAT2）。我们将转录本聚类为基因模块，并证实这些模块显著富集于亦定位于不同基因位点的生理通路中。我们针对富集α细胞（α-cells）特异性转录本的模块，以及富集δ细胞（δ-cells）特异性转录本的模块，分别鉴定并定位了其调控位点。但未发现任何模块富集β细胞（β-cells）特异性转录本，这反映了β细胞群体内部的异质性。一个富集与支链氨基酸代谢（branched chain amino acid metabolism）相关转录本的模块，与反映胰岛素抵抗（insulin resistance）的临床性状呈现最强的相关性。尽管本研究中的小鼠未表现出显性糖尿病症状，但通过对饮食诱导应激状态下胰岛基因表达的分析，我们成功鉴定出与糖尿病相关临床性状存在关联的基因与通路。本研究分析显示，小鼠中与糖尿病相关的基因位点与人类群体中鉴定出的相关位点具有高度一致性，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。