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. 2012;7(12):e52535.
doi: 10.1371/journal.pone.0052535. Epub 2012 Dec 26.

Genome-wide search for gene-gene interactions in colorectal cancer

Shuo Jiao  1 , 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 Hayes, Brian 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
Affiliations

Genome-wide search for gene-gene interactions in colorectal cancer

Shuo Jiao et al. PLoS One. 2012.

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Forest plot for meta-analysis results of GxG between rs10795668 and rs367615.
Box sizes are proportional to the inverse variance for each study and the lines depict the confidence intervals. The diamonds represent the fixed effects meta-analysis results, with the width of the diamond representing the confidence interval. The results of two advanced adenoma studies (HPFS Adv Adnm and NHS Adv Adnm) are shown at the bottom but not incorporated in the meta-analysis.
Figure 2
Figure 2. Regional interaction association plot for interacting region 5q21 with known CRC locus rs10795668.
The left y-axis shows the -log10 of the meta-analysis interaction p value. The right y-axis shows the recombination rate. Each dot on the plot represents the result for one SNP. The diamond dot represents SNP rs367615 and the round dots represent other SNPs. Difference colors of SNPs indicate different LD strength between the corresponding SNP and rs367615, measured by r2. The bottom of the figure shows the genes in the plotted region.
Figure 3
Figure 3. Forest plot for meta-analysis results of GxG between rs1571218 and rs10879357.
Box sizes are proportional to the inverse variance for each study and the lines depict the confidence intervals. The diamonds represent the fixed effects meta-analysis results, with the width of the diamond representing the confidence interval. The results of two advanced adenoma studies (HPFS Adv Adnm and NHS Adv Adnm) are shown at the bottom but not incorporated in the meta-analysis.
See this image and copyright information in PMC

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