Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues

Mingfeng Zhang, Soren Lykke-Andersen, Bin Zhu, Wenming Xiao, Jason W. Hoskins, Xijun Zhang, Lauren M. Rost, Irene Collins, Martijn Van De Bunt, Jinping Jia, Hemang Parikh, Tongwu Zhang, Lei Song, Ashley Jermusyk, Charles C. Chung, Weiyin Zhou, Gail L. Matters, Robert C. Kurtz, Meredith Yeager, Torben Heick JensenKevin M. Brown, Halit Ongen, William R. Bamlet, Bradley A. Murray, Mark I. McCarthy, Stephen J. Chanock, Nilanjan Chatterjee, Brian M. Wolpin, Jill P. Smith, Sara H. Olson, Gloria M. Petersen, Jianxin Shi, Laufey Amundadottir

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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 â '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.

Original languageEnglish (US)
Pages (from-to)521-533
Number of pages13
JournalGut
Volume67
Issue number3
DOIs
StatePublished - Mar 2018

Keywords

  • Gene expression
  • RNA-seq
  • allele specific expression.
  • eQTL
  • pancreas

ASJC Scopus subject areas

  • Gastroenterology

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    Zhang, M., Lykke-Andersen, S., Zhu, B., Xiao, W., Hoskins, J. W., Zhang, X., Rost, L. M., Collins, I., Bunt, M. V. D., Jia, J., Parikh, H., Zhang, T., Song, L., Jermusyk, A., Chung, C. C., Zhou, W., Matters, G. L., Kurtz, R. C., Yeager, M., ... Amundadottir, L. (2018). Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues. Gut, 67(3), 521-533. https://doi.org/10.1136/gutjnl-2016-313146