Regulome‐wide association study identifies genetically driven accessible regions associated with pancreatic cancer risk

Abstract Genome‐wide association studies (GWAS) have identified two dozen genetic variants that are associated with the risk of pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy. However, a majority of these variants are located in noncoding regions of the genome, which limits the translation of GWAS findings into clinical applications. The regulome‐wide association study (RWAS) is a recently developed method for identifying TF binding‐induced accessibility regions for diseases. However, their potential connection to PDAC has yet to be fully explored. We evaluated the associations between genetically predicted levels of chromatin accessibility and risk of PDAC by using pan‐cancer chromatin accessibility genetic prediction models. Our analysis included 8275 cases and 6723 controls from the PanScan (I, II, and III) and PanC4 consortia. To further refine our results, we also integrated genes associated to allele‐specific accessibility quantitative trait loci (as‐aQTL) and TF motifs located in the as‐aQTL. We found that 50 chromatin accessibility features were associated with PDAC risk at a false discovery rate (FDR) of less than 0.05. A total of 28 RWAS peaks were identified as conditionally significant. By integrating the results from as‐aQTL, motif analysis, and RWAS, we identified candidate causal regulatory elements for two potential chromatin accessibility regions (THCA_89956 and ESCA_89167) that are associated with PDAC risk. Our study identified chromatin accessibility features in noncoding genomic regions that are associated with PDAC risk. We also predicted the associated genes and disrupt motifs. Our findings provide new insights into the regulatory mechanisms of noncoding regions for pancreatic tumorigenesis.