Analysis of heritability and genetic architecture of Pancreatic Cancer: A PanC4 Study

Background:Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. Identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritabilityof pancreatic cancerand partition the heritabilityby variant frequencies and functional annotations. Methods:Analysis using the genome-based restricted maximum likelihoodmethod (GREML) was conducted on Pancreatic CancerCase-Control Consortium (PanC4) genome-wide association study data on 3,568 pancreatic cancercases and 3,363 controls of European Ancestry. Results:Applying LD- and MAF-stratified GREML (GREML-LDMS) to imputated GWAS data, we estimated the overall heritabilityof pancreatic cancerto be 21.2% (s.e. = 4.8%). Across the functional groups (intronic, intergenic, coding and regulatory variants), intronic variants account for most of the estimated heritability(12.4%). Previously identified GWAS loci explained 4.1% of the total phenotypic variation of pancreatic cancer. Mutations in hereditary pancreaticcancer susceptibility genes are present in 4-10% of pancreatic cancerpatients, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer. Conclusions:While higher than previous studies, our estimated 21.2% overall heritabilitymay still be downwardly biased due to the inherent limitation that heritablity due to individually rare variants in a gene with a substantive ovarll impact on disease are not captured in these commonly used methods Impact:Our estimate of pancreatic cancer heritabilityestimates indicate both rare and common variants contribute to missing heritability, while suggesing caution when using this approach to quantify the impact of rare variants.