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.