• Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
• Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
• Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
• Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
• Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
• Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
• Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
• Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
• Department of Medicine, Georgetown University Hospital, Washington, DC, and Department of Medicine, Penn State University College of Medicine, Hershey PA, USA.

Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10^-11, OR = 1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r²=0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (β = 0.26, P = 0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ∼6 kb upstream of DIS3 Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay.