A phenome-wide Mendelian randomization study of pancreatic cancer using summary genetic data

Background: The 5-year mortality rate for pancreatic cancer is among the highest of all cancers. Greater understanding of underlying causes could inform population-wide intervention strategies for prevention. Summary genetic data from genomewide association studies (GWAS) have become available for thousands of phenotypes. These data can be exploited in Mendelian randomization (MR) phenome-wide association studies (PheWAS) to efficiently screen the phenome for potential determinants of disease risk. Methods: We conducted an MR-PheWAS of pancreatic cancer using 486 phenotypes, proxied by 9,124 genetic variants, and summary genetic data from a GWAS of pancreatic cancer (7,110 cancer cases, 7,264 controls). ORs and 95% confidence intervals per 1 SD increase in each phenotype were generated. Results: We found evidence that previously reported risk factors of body mass index (BMI; 1.46; 1.20-1.78) and hip circumference (1.42; 1.21-1.67) were associated with pancreatic cancer. We also found evidence of novel associations with metabolites that have not previously been implicated in pancreatic cancer: ADpSGEGDFXAEGGGVR*, a fibrinogen-cleavage peptide (1.60; 1.31-1.95), and O-sulfo-L-tyrosine (0.58; 0.46-0.74). An inverse association was also observed with lung adenocarcinoma (0.63; 0.54-0.74). Conclusions: Markers of adiposity (BMI and hip circumference) are potential intervention targets for pancreatic cancer prevention. Further clarification of the causal relevance of the fibrinogen-cleavage peptides and O-sulfo-L-tyrosine in pancreatic cancer etiology is required, as is the basis of our observed association with lung adenocarcinoma. Impact: For pancreatic cancer, MR-PheWAS can augment existing risk factor knowledge and generate novel hypotheses to investigate.