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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere52535
JournalPloS one
Volume7
Issue number12
DOIs
StatePublished - Dec 29 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Jiao, S., Hsu, L., Berndt, S., Bézieau, S., Brenner, H., Buchanan, D., Caan, B. J., Campbell, P. T., Carlson, C. S., Casey, G., Chan, A. T., Chang-Claude, J., Chanock, S., Conti, D. V., Curtis, K. R., Duggan, D., Gallinger, S., Gruber, S. B., Harrison, T. A., ... Peters, U. (2012). Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer. PloS one, 7(12), [e52535]. https://doi.org/10.1371/journal.pone.0052535