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 Jensen; Kevin 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

doi:10.1136/gutjnl-2016-313146

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

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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 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 language	English (US)
Pages (from-to)	521-533
Number of pages	13
Journal	Gut
Volume	67
Issue number	3
DOIs	https://doi.org/10.1136/gutjnl-2016-313146
State	Published - Mar 2018

All Science Journal Classification (ASJC) codes

Gastroenterology

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10.1136/gutjnl-2016-313146

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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

@article{bd77bf82006d49e8bc91183f003c97d7,

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 {\^a} '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.",

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

note = "Publisher Copyright: {\textcopyright} 2018 Author(s).",

year = "2018",

month = mar,

doi = "10.1136/gutjnl-2016-313146",

language = "English (US)",

volume = "67",

pages = "521--533",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "3",

}

Zhang, M, Lykke-Andersen, S, Zhu, B, Xiao, W, Hoskins, JW, Zhang, X, Rost, LM, Collins, I, Bunt, MVD, Jia, J, Parikh, H, Zhang, T, Song, L, Jermusyk, A, Chung, CC, Zhou, W, Matters, GL, Kurtz, RC, Yeager, M, Jensen, TH, 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 2018, 'Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues', Gut, vol. 67, no. 3, pp. 521-533. https://doi.org/10.1136/gutjnl-2016-313146

TY - JOUR

T1 - Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues

AU - Zhang, Mingfeng

AU - Lykke-Andersen, Soren

AU - Zhu, Bin

AU - Xiao, Wenming

AU - Hoskins, Jason W.

AU - Zhang, Xijun

AU - Rost, Lauren M.

AU - Collins, Irene

AU - Bunt, Martijn Van De

AU - Jia, Jinping

AU - Parikh, Hemang

AU - Zhang, Tongwu

AU - Song, Lei

AU - Jermusyk, Ashley

AU - Chung, Charles C.

AU - Zhou, Weiyin

AU - Matters, Gail L.

AU - Kurtz, Robert C.

AU - Yeager, Meredith

AU - Jensen, Torben Heick

AU - Brown, Kevin M.

AU - Ongen, Halit

AU - Bamlet, William R.

AU - Murray, Bradley A.

AU - McCarthy, Mark I.

AU - Chanock, Stephen J.

AU - Chatterjee, Nilanjan

AU - Wolpin, Brian M.

AU - Smith, Jill P.

AU - Olson, Sara H.

AU - Petersen, Gloria M.

AU - Shi, Jianxin

AU - Amundadottir, Laufey

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=85026419018&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2016-313146

DO - 10.1136/gutjnl-2016-313146

M3 - Article

C2 - 28634199

AN - SCOPUS:85026419018

SN - 0017-5749

VL - 67

SP - 521

EP - 533

JO - Gut

JF - Gut

IS - 3

ER -

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

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