Analysis of heritability and genetic architecture of pancreatic cancer: A PanC4 study Journal Article
| Authors: | Chen, F.; Childs, E. J.; Mocci, E.; Bracci, P.; Gallinger, S.; Li, D.; Neale, R. E.; Olson, S. H.; Scelo, G.; Bamlet, W. R.; Blackford, A. L.; Borges, M.; Brennan, P.; Chaffee, K. G.; Duggal, P.; Hassan, M. J.; Holly, E. A.; Hung, R. J.; Goggins, M. G.; Kurtz, R. C.; Oberg, A. L.; Orlow, I.; Yu, H.; Petersen, G. M.; Risch, H. A.; Klein, A. P. |
| Article Title: | Analysis of heritability and genetic architecture of pancreatic cancer: A PanC4 study |
| Abstract: | 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 1⁄4 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. © 2019 American Association for Cancer Research. |
| Journal Title: | Cancer Epidemiology Biomarkers and Prevention |
| Volume: | 28 |
| Issue: | 7 |
| ISSN: | 1055-9965 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-07-01 |
| Start Page: | 1238 |
| End Page: | 1245 |
| Language: | English |
| DOI: | 10.1158/1055-9965.Epi-18-1235 |
| PUBMED: | 31015203 |
| PROVIDER: | scopus |
| PMCID: | PMC6606380 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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