Characterising -regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues.
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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. |
Year of Publication | 2018
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Journal | Gut
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Volume | 67
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Issue | 3
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Pages | 521-533
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Date Published | 2018 03
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ISSN | 1468-3288
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DOI | 10.1136/gutjnl-2016-313146
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PubMed ID | 28634199
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PubMed Central ID | PMC5762429
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Grant list | ZIA 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
P50 CA102701 / CA / NCI 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
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