Abstract
Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10−5) compared with the additive effects (p>10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.
Highlights
Pancreatic cancer ranks fourth for cancer-related deaths in western countries and is projected to become the second by 2030 [1, 2]
In the first phase, which was conducted at a genome-wide scale, we re-analyzed the data from the PanScan+PanC4 genome-wide association studies (GWASs) dataset according to a recessive model of inheritance, and we observed six single nucleotide polymorphisms (SNPs) that showed specific recessive associations with pancreatic ductal adenocarcinoma (PDAC) risk with p10-3 using the additive model (Figure 1, Supplementary Table 2)
The associations of the genotyped SNPs with PDAC risk under the additive and recessive genetic models are shown in Figure 1 (Supplementary Table 2)
Summary
Pancreatic cancer ranks fourth for cancer-related deaths in western countries and is projected to become the second by 2030 [1, 2] It is a very deadly disease with the mortality rate closely approaching to the incidence rate. The identified SNPs explain only 4.1% of the total phenotypic variance of pancreatic cancer, which do not fully account for the overall 21.2% estimated genetic heritability [16]. This can be explained by the relatively small effect sizes of the individual risk loci, and by the strict multiple testing correction required for GWAS (typically p < 5x10-8), which is likely to result in a large number of false negatives
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