Zhang Mingfeng, Lykke-Andersen Soren, Zhu Bin, Xiao Wenming, Hoskins Jason W, Zhang Xijun, Rost Lauren M, Collins Irene, Bunt Martijn van de, Jia Jinping, Parikh Hemang, Zhang Tongwu, Song Lei, Jermusyk Ashley, Chung Charles C, Zhu Bin, Zhou Weiyin, Matters Gail L, Kurtz Robert C, Yeager Meredith, Jensen Torben Heick, Brown Kevin M, Ongen Halit, Bamlet William R, Murray Bradley A, McCarthy Mark I, Chanock Stephen J, Chatterjee Nilanjan, Wolpin Brian M, Smith Jill P, Olson Sara H, Petersen Gloria M, Shi Jianxin, Amundadottir Laufey
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
Gut. 2018 Mar;67(3):521-533. doi: 10.1136/gutjnl-2016-313146. Epub 2017 Jun 20.
To elucidate the genetic architecture of gene expression in pancreatic tissues.
We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison.
We identified 38 615 -eQTLs (in 484 genes) in histologically normal tissues and 39 713 -eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant -eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of -eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with expression in histologically normal (p=5.8×10) and tumour-derived (p=8.3×10) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in (exon 6) suggested that nonsense-mediated decay (NMD) of the 'O' mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the 'O' mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL.
We have identified -eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.
阐明胰腺组织中基因表达的遗传结构。
我们使用RNA测序和相应的千人基因组推算种系基因型，对组织学正常的胰腺组织样本（n = 95）进行了表达定量性状基因座（eQTL）分析。纳入了来自癌症基因组图谱的胰腺肿瘤衍生组织样本（n = 115）的数据进行比较。
我们在组织学正常组织中鉴定出38615个eQTL（存在于484个基因中），在肿瘤衍生组织中鉴定出39713个eQTL（存在于237个基因中）（错误发现率<0.1），在转录起始位点附近观察到最强的效应。分别约有23%和42%具有显著eQTL的基因似乎分别是肿瘤衍生组织和正常组织特有的。在非编码调控区域发现eQTL变体有显著富集，尤其是在胰腺组织中（1.53倍至3.12倍，p≤0.0001），表明其具有组织特异性功能相关性。9q34.2上一个常见的胰腺癌风险基因座（rs687289）与组织学正常组织（p = 5.8×10）和肿瘤衍生组织（p = 8.3×10）中的表达相关。该变体与ABO（第6外显子）中产生O血型的缺失变体之间的高度连锁不平衡表明，“O”mRNA的无义介导衰变（NMD）可能解释这一发现。然而，关键NMD调节因子的敲低并未影响“O”mRNA的衰变，表明受胰腺癌风险等位基因影响的基因调控元件可能是eQTL的基础。
我们已经鉴定出代表胰腺中潜在功能调控变体的eQTL，并生成了一个丰富的数据集，用于进一步研究胰腺组织中的基因表达及其调控。
