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=5.8×10−8) 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.
- gene expression
- allele specific expression.
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Contributors LA and MZ had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of data analysis. LA: study concept and design. MZ, BZ, WX, JWH, MvdB, HP, MIM, SJC, NC, JPS, SHO, GMP and JS: contribution to study design. MZ, BZ, WX, IC, JS and LA: acquisition of data. MZ, SLA, BZ, WX, JWH, XZ, LMR, MvdB, JJ, HP, TZ, LS, AJ, CCC, BZ, WZ, THJ, MIM, NC, BMW, JPS, SHO, GMP, JS and LA: analysis and interpretation of data. MZ and LA: drafting the manuscript. SJC and KMB: critical review of the manuscript. MZ, BZ, JS and LA: statistical analysis. BAM, WRB, HO, MY, RCK, GLM, IC and LA: administrative, technical or material support. LA: funding and study supervision.
Funding This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. MvdB is supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. MIM is a Wellcome Trust Senior Investigator and is supported by Wellcome Trust awards (#098381, 090532) and NIH grants (U01DK105535). SO at MSKCC is also supported by P30CA008748, C.Thompson, PI.
Competing interests None declared.
Patient consent Consents were signed at each institution that participated in the research (Mayo Clinic and Memorial Sloan Kettering Cancer Center).
Ethics approval National Cancer Institute/NIH, Mayo Clinic, Memorial Sloan Kettering Cancer Center, Penn State University.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data from RNA sequencing and GWAS genotyping will be deposited in dbGAP and are available from the authors upon reasonable request.