Genome-wide association studies (GWAS) are a powerful tool for detecting variants
associated with complex traits and can help risk stratification and prevention strategies
against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance
threshold commonly used makes it likely that many true risk loci are missed. Functional
annotation of GWAS polymorphisms is a proven strategy to identify additional risk
loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory
regions [transcription factor binding sites (TFBSs) and enhancers] that could change
the expression profile of multiple genes they act upon and thereby modify PDAC risk.
We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and
the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication
population). We identified four associations that reached study-wide statistical significance
in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13,
p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1
× 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and
rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with
the most significant association, rs2472632, is located in an enhancer predicted to
target the coiled-coil domain containing 34 oncogene. Our results provide new insights
into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory
regions and demonstrating the usefulness of functional prioritization to identify
loci associated with PDAC risk.
