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

被引：53

作者：

Chen, Fei ^{[1
]}

Childs, Erica J. ^{[2
]}

Mocci, Evelina ^{[2
]}

Bracci, Paige ^{[3
]}

Gallinger, Steven ^{[4
]}

Li, Donghui ^{[5
]}

Neale, Rachel E. ^{[6
]}

Olson, Sara H. ^{[7
]}

Scelo, Ghislaine ^{[8
]}

Bamlet, William R. ^{[9
]}

Blackford, Amanda L. ^{[2
]}

Borges, Michael ^{[10
]}

Brennan, Paul ^{[8
]}

Chaffee, Kari G. ^{[9
]}

Duggal, Priya ^{[1
]}

Hassan, Manal J. ^{[5
]}

Holly, Elizabeth A. ^{[3
]}

Hung, Rayjean J. ^{[11
]}

Goggins, Michael G. ^{[10
]}

Kurtz, Robert C. ^{[12
]}

Oberg, Ann L. ^{[9
]}

Orlow, Irene ^{[7
]}

Yu, Herbert ^{[13
]}

Petersen, Gloria M. ^{[9
]}

Risch, Harvey A. ^{[14
]}

Klein, Alison P. ^{[1
,2
,10
]}

机构：

[1] Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[2] Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA

[3] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA

[4] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON, Canada

[5] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA

[6] QIMR Berghofer Med Res Inst, Dept Populat Hlth, Brisbane, Qld, Australia

[7] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[8] IARC, Lyon, France

[9] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA

[10] Johns Hopkins Sch Med, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD USA

[11] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[12] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[13] Univ Hawaii, Ctr Canc, Epidemiol Program, Honolulu, HI 96822 USA

[14] Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA

来源：

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION | 2019年 / 28卷 / 07期

基金：

英国医学研究理事会; 美国国家卫生研究院; 澳大利亚国家健康与医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; MISSING HERITABILITY; PREDISPOSITION GENES; SUSCEPTIBILITY LOCI; MUTATIONS; PREVALENCE; VARIANTS; TWINS; RISK;

D O I：

10.1158/1055-9965.EPI-18-1235

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：1238 / 1245

页数：8

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