Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer

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Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer

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Title: Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer
Author: Jiao, Shuo; Hsu, Li; Berndt, Sonja; Bézieau, Stéphane; Brenner, Hermann; Buchanan, Daniel; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew Tan; Chang-Claude, Jenny; Chanock, Stephen; Conti, David V.; Curtis, Keith R.; Duggan, David; Gallinger, Steven; Gruber, Stephen B.; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Hutter, Carolyn M.; Jackson, Rebecca D.; Jenkins, Mark A.; Kantor, Elizabeth D.; Kolonel, Laurence N.; Küry, Sébastien; Le Marchand, Loic; Lemire, Mathieu; Newcomb, Polly A.; Potter, John D.; Qu, Conghui; Rosse, Stephanie A.; Schoen, Robert E.; Schumacher, Fred R.; Seminara, Daniela; Slattery, Martha L.; Ulrich, Cornelia M.; Zanke, Brent W.; Peters, Ulrike

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Citation: Jiao, Shuo, Li Hsu, Sonja Berndt, Stéphane Bézieau, Hermann Brenner, Daniel Buchanan, Bette J. Caan, et al. 2012. Genome-wide search for gene-gene interactions in colorectal cancer. PLoS ONE 7(12): e52535.
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Abstract: Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<\(10^{−4}\)). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19×\(10^{−8}\). Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51×\(10^{−6}\); Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.
Published Version: doi:10.1371/journal.pone.0052535
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