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Gut DOI:10.1136/gutjnl-2016-313146

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

Publication TypeJournal Article
Year of Publication2018
AuthorsZhang, M, Lykke-Andersen, S, Zhu, B, Xiao, W, Hoskins, JW, Zhang, X, Rost, LM, Collins, I, van de Bunt, M, Jia, J, Parikh, H, Zhang, T, Song, L, Jermusyk, A, Chung, CC, Zhu, B, Zhou, W, Matters, GL, Kurtz, RC, Yeager, M, Jensen, THeick, Brown, KM, Ongen, H, Bamlet, WR, Murray, BA, McCarthy, MI, Chanock, SJ, Chatterjee, N, Wolpin, BM, Smith, JP, Olson, SH, Petersen, GM, Shi, J, Amundadottir, L
JournalGut
Volume67
Issue3
Pages521-533
Date Published2018 03
ISSN1468-3288
KeywordsABO Blood-Group System, Alleles, Chromosomes, Human, Pair 9, Gene Expression, Genome-Wide Association Study, Genotype, Humans, Nonsense Mediated mRNA Decay, Pancreas, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, RNA, Neoplasm, Sequence Analysis, RNA, Transcriptome
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 -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.CONCLUSIONS: 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.

DOI10.1136/gutjnl-2016-313146
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28634199?dopt=Abstract

Alternate JournalGut
PubMed ID28634199
PubMed Central IDPMC5762429
Grant ListZIA CP010193-06 / NULL / Intramural NIH HHS / United States
ZIA CP010193-05 / ImNIH / Intramural NIH HHS / United States
ZIA CP010193-09 / NULL / Intramural NIH HHS / United States
Z99 CA999999 / ImNIH / Intramural NIH HHS / United States
ZIA CP010193-09 / ImNIH / Intramural NIH HHS / United States
ZIA CP010193-7 / ImNIH / Intramural NIH HHS / United States
R01 DA006227 / DA / NIDA NIH HHS / United States
Z99 CA999999 / NULL / Intramural NIH HHS / United States
R01 MH101782 / MH / NIMH NIH HHS / United States
R01 MH101810 / MH / NIMH NIH HHS / United States
R01 MH101819 / MH / NIMH NIH HHS / United States
ZIA CP010193-05 / NULL / Intramural NIH HHS / United States
R01 MH090936 / MH / NIMH NIH HHS / United States
ZIA CP010193-07 / NULL / Intramural NIH HHS / United States
U01 DK105535 / DK / NIDDK NIH HHS / United States
ZIA CP010193-06 / ImNIH / Intramural NIH HHS / United States
ZIA CP010193-10 / ImNIH / Intramural NIH HHS / United States
ZIA CP010193-08 / ImNIH / Intramural NIH HHS / United States
ZIA CP010193-07 / ImNIH / Intramural NIH HHS / United States
R01 MH090951 / MH / NIMH NIH HHS / United States
ZIA CP010193-7 / NULL / Intramural NIH HHS / United States
R01 MH101820 / MH / NIMH NIH HHS / United States
R01 MH101825 / MH / NIMH NIH HHS / United States
R01 MH090948 / MH / NIMH NIH HHS / United States
R01 MH090941 / MH / NIMH NIH HHS / United States
/ / Wellcome Trust / United Kingdom
ZIA CP010193-08 / NULL / Intramural NIH HHS / United States
R01 MH101822 / MH / NIMH NIH HHS / United States
HHSN261200800001C / RC / CCR NIH HHS / United States
R01 MH090937 / MH / NIMH NIH HHS / United States
ZIA CP010193-10 / NULL / Intramural NIH HHS / United States
HHSN268201000029C / HL / NHLBI NIH HHS / United States
HHSN261200800001E / CA / NCI NIH HHS / United States
R01 MH101814 / MH / NIMH NIH HHS / United States