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Cancer Epidemiol Biomarkers Prev. 2019 Jul;28(7):1238-1245. doi: 10.1158/1055-9965.EPI-18-1235. Epub 2019 Apr 23.

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

Author information

1
Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland.
2
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
3
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
4
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
5
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Population Health, QIMR Berghofer Medical Research Institute, Queensland, Australia.
7
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
8
International Agency for Research on Cancer (IARC), Lyon, France.
9
Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
10
Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
11
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
12
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
13
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
14
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
15
Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland. aklein1@jhmi.edu.

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 = 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.

PMID:
31015203
PMCID:
PMC6606380
[Available on 2020-07-01]
DOI:
10.1158/1055-9965.EPI-18-1235

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