Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using TALLYHO x C57BL6 F2 mice

Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The TALLYHO/JngJ (TH) mouse is a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. To determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels, as well as body weights. Fat pad and carcass weights were measured at 24 weeks after sacrificing the mice. The F2 mice were genotyped genome-wide for 68 markers. Of 393 genotyped F2 mice, 16 were chosen from the extremes of the triglyceride distribution (8 high and 8 low), and liver, pancreas, muscle and adipose tissue were measured for gene expression. Gene expression quantitative trait locus (eQTL) analysis aided in selection of candidates underlying hyperlipidemia, diabetes and obesity QTLs. We identified several genetic loci that affected quantitative variation in plasma lipid and glucose levels and obesity traits. 16 (8 high and 8 low) out of 393 F2 mice were chosen from the extremes of the triglyceride distribution, excluding overtly diabetic mice, and liver, pancreas, muscle and adipose tissue were measured for gene expression. In addition to data from the 64 microarrays on the 16 mice, a supplemental file with phenotypes and marker genotypes is provided for all mice as a supplementary file on the Series record (below). Mouse identification numbers are included to connect the data files.2型糖尿病（Type 2 diabetes, T2D）是人类最常见的糖尿病类型，与血脂异常和肥胖紧密关联，而后者会加重T2D相关的死亡率与发病率。TALLYHO/JngJ（TH）小鼠是一种多基因2型糖尿病模型，其特征为肥胖、高胰岛素血症、葡萄糖摄取与耐受受损、高脂血症及高血糖。为明确TH小鼠中与这些T2D相关表型相关的遗传因素，我们将TH小鼠与C57BL/6J（B6）小鼠进行杂交繁育。分别在8、12、16、20及24周龄时，对亲代、F1及F2代小鼠进行表型分析，检测其4小时禁食状态下的血浆甘油三酯、胆固醇、胰岛素及葡萄糖水平，同时记录体重。在小鼠饲养至24周龄处死后，测量其脂肪垫重量与胴体重量。对F2代小鼠采用68个遗传标记进行全基因组基因分型。在393只完成全基因组基因分型的F2代小鼠中，我们从甘油三酯分布的极端区间选取了16只（8只高值、8只低值），并排除了显性糖尿病小鼠，随后对其肝脏、胰腺、肌肉及脂肪组织进行基因表达检测。基因表达数量性状位点（expression quantitative trait locus, eQTL）分析可辅助筛选高脂血症、糖尿病及肥胖数量性状位点的候选基因。本研究鉴定出多个可影响血浆脂质、葡萄糖水平及肥胖性状数量变异的遗传位点。除了这16只小鼠的64张基因表达微阵列数据外，本数据集还为所有小鼠提供了包含表型数据与标记基因型的补充文件，该补充文件已上传至系列记录（见下文）。数据文件中包含小鼠编号，用于关联各数据文件。