Analysis of heritability and genetic architecture of pancreatic cancer: A PANC4 study

Fei Chen, Erica J. Childs, Evelina Mocci, Paige Bracci, Steven Gallinger, Donghui Li, Rachel E. Neale, Sara H. Olson, Ghislaine Scelo, William R. Bamlet, Amanda L. Blackford, Michael Borges, Paul Brennan, Kari G. Chaffee, Priya Duggal, Manal J. Hassan, Elizabeth A. Holly, Rayjean J. Hung, Michael G. Goggins, Robert C. KurtzAnn L. Oberg, Irene Orlow, Herbert Yu, Gloria M. Petersen, Harvey A. Risch, Alison P. Klein

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1238-1245
Number of pages8
JournalCancer Epidemiology Biomarkers and Prevention
Volume28
Issue number7
DOIs
StatePublished - Jan 1 2019

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Pancreatic Neoplasms
Genome-Wide Association Study
Genome
Neoplasm Genes
Linkage Disequilibrium
Gene Frequency
Cause of Death
Mutation

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

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Analysis of heritability and genetic architecture of pancreatic cancer : A PANC4 study. / Chen, Fei; Childs, Erica J.; Mocci, Evelina; Bracci, Paige; Gallinger, Steven; Li, Donghui; Neale, Rachel E.; Olson, Sara H.; Scelo, Ghislaine; Bamlet, William R.; Blackford, Amanda L.; Borges, Michael; Brennan, Paul; Chaffee, Kari G.; Duggal, Priya; Hassan, Manal J.; Holly, Elizabeth A.; Hung, Rayjean J.; Goggins, Michael G.; Kurtz, Robert C.; Oberg, Ann L.; Orlow, Irene; Yu, Herbert; Petersen, Gloria M.; Risch, Harvey A.; Klein, Alison P.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 28, No. 7, 01.01.2019, p. 1238-1245.

Research output: Contribution to journalArticle

Chen, F, Childs, EJ, Mocci, E, Bracci, P, Gallinger, S, Li, D, Neale, RE, Olson, SH, Scelo, G, Bamlet, WR, Blackford, AL, Borges, M, Brennan, P, Chaffee, KG, Duggal, P, Hassan, MJ, Holly, EA, Hung, RJ, Goggins, MG, Kurtz, RC, Oberg, AL, Orlow, I, Yu, H, Petersen, GM, Risch, HA & Klein, AP 2019, 'Analysis of heritability and genetic architecture of pancreatic cancer: A PANC4 study', Cancer Epidemiology Biomarkers and Prevention, vol. 28, no. 7, pp. 1238-1245. https://doi.org/10.1158/1055-9965.EPI-18-1235
Chen, Fei ; Childs, Erica J. ; Mocci, Evelina ; Bracci, Paige ; Gallinger, Steven ; Li, Donghui ; Neale, Rachel E. ; Olson, Sara H. ; Scelo, Ghislaine ; Bamlet, William R. ; Blackford, Amanda L. ; Borges, Michael ; Brennan, Paul ; Chaffee, Kari G. ; Duggal, Priya ; Hassan, Manal J. ; Holly, Elizabeth A. ; Hung, Rayjean J. ; Goggins, Michael G. ; Kurtz, Robert C. ; Oberg, Ann L. ; Orlow, Irene ; Yu, Herbert ; Petersen, Gloria M. ; Risch, Harvey A. ; Klein, Alison P. / Analysis of heritability and genetic architecture of pancreatic cancer : A PANC4 study. In: Cancer Epidemiology Biomarkers and Prevention. 2019 ; Vol. 28, No. 7. pp. 1238-1245.
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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.",
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T1 - Analysis of heritability and genetic architecture of pancreatic cancer

T2 - A PANC4 study

AU - Chen, Fei

AU - Childs, Erica J.

AU - Mocci, Evelina

AU - Bracci, Paige

AU - Gallinger, Steven

AU - Li, Donghui

AU - Neale, Rachel E.

AU - Olson, Sara H.

AU - Scelo, Ghislaine

AU - Bamlet, William R.

AU - Blackford, Amanda L.

AU - Borges, Michael

AU - Brennan, Paul

AU - Chaffee, Kari G.

AU - Duggal, Priya

AU - Hassan, Manal J.

AU - Holly, Elizabeth A.

AU - Hung, Rayjean J.

AU - Goggins, Michael G.

AU - Kurtz, Robert C.

AU - Oberg, Ann L.

AU - Orlow, Irene

AU - Yu, Herbert

AU - Petersen, Gloria M.

AU - Risch, Harvey A.

AU - Klein, Alison P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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