Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues Journal Article
| Authors: | Zhang, M.; Lykke-Andersen, S.; Zhu, B.; Xiao, W.; Hoskins, J. W.; Zhang, X.; Rost, L. M.; Collins, I.; van de Bunt, M.; Jia, J.; Parikh, H.; Zhang, T.; Song, L.; Jermusyk, A.; Chung, C. C.; Zhu, B.; Zhou, W.; Matters, G. L.; Kurtz, R. C.; Yeager, M.; Jensen, T. H.; Brown, K. M.; Ongen, H.; Bamlet, W. R.; Murray, B. A.; McCarthy, M. I.; Chanock, S. J.; Chatterjee, N.; Wolpin, B. M.; Smith, J. P.; Olson, S. H.; Petersen, G. M.; Shi, J.; Amundadottir, L. |
| Article Title: | Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues |
| 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. © 2018 Author(s). |
| Keywords: | controlled study; human tissue; human cell; sequence analysis; single nucleotide polymorphism; gene deletion; genetics; polymorphism, single nucleotide; cancer risk; pancreas cancer; pancreatic neoplasms; pancreas; allele; gene expression; blood group abo system; genotype; abo blood-group system; alleles; chromosomes, human, pair 9; genetic variation; genome-wide association study; gene function; genetic transcription; histology; rna; messenger rna; gene identification; pancreas tumor; sequence analysis, rna; rna, neoplasm; genetic code; transcriptome; quantitative trait locus; quantitative trait loci; rna sequence; regulatory sequences, nucleic acid; chromosome 9; regulatory sequence; rna-seq; nonsense mediated mrna decay; gene knockdown; humans; human; priority journal; article; eqtl; pancreas tissue; expression quantitative trait locus; allele specific expression. |
| Journal Title: | Gut |
| Volume: | 67 |
| Issue: | 3 |
| ISSN: | 0017-5749 |
| Publisher: | BMJ Publishing Group Ltd. |
| Date Published: | 2018-03-01 |
| Start Page: | 521 |
| End Page: | 533 |
| Language: | English |
| DOI: | 10.1136/gutjnl-2016-313146 |
| PUBMED: | 28634199 |
| PROVIDER: | scopus |
| PMCID: | PMC5762429 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 April 2018 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work