Heritability and Genetic Architecture of Pancreatic Cancer

Heritability;Pancreatic Cancer;Epidemiology

Chen, FeiZandi, Peter ;

Johns Hopkins University

关键词: Heritability;    Pancreatic Cancer;    Epidemiology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60083/CHEN-DISSERTATION-2018.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Pancreatic cancer is currently the third leading cause of cancer deaths in the US. Identified common susceptibility loci for pancreatic cancer only account for a small fraction of phenotypic variations, highlighting the ;;missing heritability” problem. Array heritabilities were underestimated because of the inadequate coverage on rare variants. The goal of this study was to generate a more comprehensive and less biased estimate of heritability for pancreatic cancer and to infer the genetic architecture of pancreatic cancer through genomic partitioning of the estimated heritability. In the Pancreatic Cancer Case-Control Consortium (PanC4) study of 3,568 cases and 3,363 controls, the heritability estimated from the imputed variants was 21.2% (s.e. = 4.8%). Genomic partitioning found more than one-third of the estimated heritability attributable to rare variants with minor allele frequency (MAF) < 0.01. Across the functional group of intronic, intergenic, coding and regulatory variants, intronic variants account for most estimated heritability. Identified GWAS loci explained 4.1% of the total phenotypic variations for pancreatic cancer. These findings suggest that the yet-to-be-identified rare and common variants are both key contributors to the ;;missing heritability” of pancreatic cancer, and it’s important to include both coding and regulatory regions in the search of disease-causing variants for pancreatic cancer. In the combined sample of 569 familial pancreatic cancer (FPC) cases and 754 controls from Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, whole-genome sequencing (WGS) variants explained 38.8% (s.e. = 15.7%) of total phenotypic variance for pancreatic cancer. This higher estimate of heritability for pancreatic cancer is likely a result of a more completed characterization of genetic variation across the genome in the sequencing data as well as a stronger genetic background in the FPC cases. In addition, variants in 11 established FPC genes only explained 0.4% of total phenotypic variance for pancreatic cancer in PanC4 study, which reflected the limitation of current statistical approaches in capturing the contribution of rare variants to the heritability of a trait. Findings from this study provided valuable insights into the genetic architecture of pancreatic cancer which would help understand the disease etiology and to aid in disease screening, diagnosis, prognosis and therapy.