@article{f38eaef039ff48898cb73edb78725cb7,
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 ¼ 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.",
author = "Fei Chen and Childs, {Erica J.} and Evelina Mocci and Paige Bracci and Steven Gallinger and Donghui Li and Neale, {Rachel E.} and Olson, {Sara H.} and Ghislaine Scelo and Bamlet, {William R.} and Blackford, {Amanda L.} and Michael Borges and Paul Brennan and Chaffee, {Kari G.} and Priya Duggal and Hassan, {Manal J.} and Holly, {Elizabeth A.} and Hung, {Rayjean J.} and Goggins, {Michael G.} and Kurtz, {Robert C.} and Oberg, {Ann L.} and Irene Orlow and Herbert Yu and Petersen, {Gloria M.} and Risch, {Harvey A.} and Klein, {Alison P.}",
note = "Funding Information: The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701 PI: G. Petersen). Funding Information: This work was supported by RO1CA154823 (PI: A.P. Klein). Genotyping Services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University; contract number HHSN268201100011I (PI: Valle awarded to A.P. Klein). The IARC/Central Europe study was supported by a grant from the U.S. National Cancer Institute at the National Institutes of Health (R03 CA123546-02 PI: Brennan support to G. Scelo) and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, MH CZ-DRO-MMCI 00209805 PI: Kollavara Support to G. Scelo). The work at Johns Hopkins University was supported by the NCI grants P50CA062924 (PI: A. Klein), P30CA006973 (PI: Nelson support to A. Klein), and R01CA97075 (PI: Petersen support to A. Klein and M. Goggins). The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701 PI: G. Petersen). The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry is supported by P30CA008748 (PI: C. Thompson support to S. Olson), the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation, and the Society of MSKCC. The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; grant no. 442302; PI: R. Neale). R.E. Neale is supported by a NHMRC Senior Research Fellowship (#1060183 PI: R. Neale). The UCSF pancreas study was supported by the NIH-NCI grants (R01CA1009767 PI: E. Holly, R01CA109767-S1 PI: P. Bracci) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program; the NCI's SEER Program under contract HHSN261201000140C awarded to CPIC; and the CDC's National Program of Cancer Registries, under agreement #U58DP003862-01 awarded to the California Department of Public Health. The Yale (CT) pancreas study is supported by NCI at the U.S. NIH, grant no. 5R01CA098870 (PI: H. Risch). The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. Assistance with genotype data quality control was provided by Cecelia Laurie and Cathy Laurie at University of Washington Genetic Analysis Center. F. Chen was supported by the Maryland Genetics, Epidemiology, and Medicine Training Program (MD-GEM) sponsored by the Burroughs-Wellcome Fund (PI: Duggal). Funding Information: The IARC/Central Europe study was supported by a grant from the U.S. National Cancer Institute at the National Institutes of Health (R03 CA123546-02 PI: Brennan support to G. Scelo) and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, MH CZ-DRO-MMCI 00209805 PI: Kollavara Support to G. Scelo). Funding Information: This work was supported by RO1CA154823 (PI: A.P. Klein). Genotyping Services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to the Johns Hopkins University; contract number HHSN268201100011I (PI: Valle awarded to A.P. Klein). Funding Information: The work at Johns Hopkins University was supported by the NCI grants P50CA062924 (PI: A. Klein), P30CA006973 (PI: Nelson support to A. Klein), and R01CA97075 (PI: Petersen support to A. Klein and M. Goggins). Funding Information: The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry is supported by P30CA008748 (PI: C. Thompson support to S. Olson), the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research.",
year = "2019",
doi = "10.1158/1055-9965.EPI-18-1235",
language = "English (US)",
volume = "28",
pages = "1238--1245",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "7",
}