Pathway Analysis of Genome-wide Association Study Data Highlights Pancreatic Development Genes as Susceptibility Factors for Pancreatic Cancer.

Publication Type:

Journal Article

Source:

Carcinogenesis, Volume 33, Issue 7, p.1384-90 (2012)

Keywords:

2012, Center-Authored Paper, May 2012, Public Health Sciences Division, Shared Resources, Specimen Processing Core Facility

Abstract:

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease associated SNPs whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3,851 pancreatic cancer cases and 3,934 control participants pooled from 12 cohort studies and 8 case control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response, and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019, and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO, and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), while the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G, and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response; and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.