Objective To elucidate the genetic architecture of gene expression in pancreatic tissues. Design 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. Results We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-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 cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-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 ABO expression in histologically normal (p=5.8×10−8) and tumour-derived (p=8.3×10−5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (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 ABO ‘O’ mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. Conclusions We have identified cis-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.

中文翻译：

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表征组织学正常和肿瘤来源的胰腺组织的转录组中的顺式调节变异


目的 阐明胰腺组织中基因表达的遗传结构。设计我们使用 RNA 测序和相应的 1000 个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) 进行表达数量性状基因座 (eQTL) 分析。来自癌症基因组图谱的胰腺肿瘤来源的组织样本 (n=115) 的数据也被纳入进行比较。结果 我们在组织学正常组织中鉴定出 38 615 个 cis-eQTL（在 484 个基因中），在肿瘤衍生组织中鉴定出 39 713 个 cis-eQTL（在 237 个基因中）（错误发现率 <0.1），在转录附近观察到最强的影响。启动站点。大约 23% 和 42% 具有显着顺式 eQTL 的基因似乎分别对肿瘤来源和正常来源的组织具有特异性。在非编码调控区域中注意到顺式 eQTL 变体的显着富集，特别是对于胰腺组织（1.53 倍至 3.12 倍，p≤0.0001），表明组织特异性功能相关性。 9q34.2 (rs687289) 上的一个常见胰腺癌风险位点与组织学正常 (p=5.8×10−8) 和肿瘤来源 (p=8.3×10−5) 组织中的 ABO 表达相关。该变体与 ABO（外显子 6）中产生 O 血型缺失变体之间的高度连锁不平衡表明，“O”mRNA 的无义介导的衰变（NMD）可能解释了这一发现。然而，关键 NMD 调节因子的敲低并不影响 ABO 'O' mRNA 的衰变，表明受胰腺癌风险等位基因影响的基因调节元件可能是 eQTL 的基础。 结论 我们已经鉴定出代表胰腺中潜在功能调控变异的 cis-eQTL，并生成了丰富的数据集，用于进一步研究胰腺组织中的基因表达及其调控。