Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
Nat Genet. 2011 Jun;43(6):561-4. doi: 10.1038/ng.833. Epub 2011 May 15.
Genome-wide association studies have identified many genetic variants associated with complex traits. However, at only a minority of loci have the molecular mechanisms mediating these associations been characterized. In parallel, whereas cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention. Here we show that the type 2 diabetes and high-density lipoprotein cholesterol-associated cis-acting expression quantitative trait locus (eQTL) of the maternally expressed transcription factor KLF14 acts as a master trans regulator of adipose gene expression. Expression levels of genes regulated by this trans-eQTL are highly correlated with concurrently measured metabolic traits, and a subset of the trans-regulated genes harbor variants directly associated with metabolic phenotypes. This trans-eQTL network provides a mechanistic understanding of the effect of the KLF14 locus on metabolic disease risk and offers a potential model for other complex traits.
全基因组关联研究已经确定了许多与复杂性状相关的遗传变异。然而，在这些关联中，只有少数位点的分子机制得到了描述。与此同时，尽管顺式调控基因表达的模式已经得到了广泛的探索，但人类中转录调控效应的鉴定却受到较少关注。在这里，我们表明，2 型糖尿病和高密度脂蛋白胆固醇相关的母源表达转录因子 KLF14 的顺式作用表达数量性状基因座 (eQTL) 是脂肪基因表达的主要转录调节因子。受这个转录 eQTL 调节的基因的表达水平与同时测量的代谢性状高度相关，并且一部分转录调节的基因具有与代谢表型直接相关的变体。这个转录 eQTL 网络为 KLF14 位点对代谢疾病风险的影响提供了一种机制上的理解，并为其他复杂性状提供了一个潜在的模型。
