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

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.