• Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
• Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, NIH, Frederick, MD 21702, USA.
• Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
• Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
• Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.
• Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA 30303, USA.
• Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
• Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017, USA.
• Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
• Department of Medicine, Georgetown University, Washington, DC 20057, USA.

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10^-17, OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p_GTEx = 1.40 × 10^-69, β_GTEx = 1.99; p_LTG = 1.02 × 10^-30, β_LTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10^-16, OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.