Analysis of Heritability and Genetic Architecture of Pancreatic Cancer: A PanC4 Study.

Cancer Epidemiol Biomarkers Prev 2019 Jul 23;28(7):1238-1245. Epub 2019 Apr 23.

Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland.

Background: Pancreatic cancer is the fourth-leading cause of cancer death in both men and women in the United States. The currently identified common susceptibility loci account for a small fraction of estimated heritability. We sought to estimate overall heritability of pancreatic cancer and partition the heritability by variant frequencies and functional annotations.

Methods: Analysis using the genome-based restricted maximum likelihood method (GREML) was conducted on Pancreatic Cancer Case-Control Consortium (PanC4) genome-wide association study (GWAS) data from 3,568 pancreatic cancer cases and 3,363 controls of European Ancestry.

Results: Applying linkage disequilibrium- and minor allele frequency-stratified GREML (GREML-LDMS) method to imputed GWAS data, we estimated the overall heritability of pancreatic cancer to be 21.2% (SE = 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 pancreatic cancer susceptibility genes are present in 4% to 10% of patients with pancreatic cancer, yet our GREML-LDMS results suggested these regions explain only 0.4% of total phenotypic variance for pancreatic cancer.

Conclusions: Although higher than previous studies, our estimated 21.2% overall heritability may still be downwardly biased due to the inherent limitation that the contribution of rare variants in genes with a substantive overall impact on disease are not captured when applying these commonly used methods to imputed GWAS data.

Impact: Our work demonstrated the importance of rare and common variants in pancreatic cancer risk.

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Source
http://cebp.aacrjournals.org/lookup/doi/10.1158/1055-9965.EP
Publisher Site
http://dx.doi.org/10.1158/1055-9965.EPI-18-1235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606380PMC
July 2019
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