Meta-analysis of new genome-wide association studies of colorectal cancer risk

Abstract

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.

Figure 1. Regional association results and LD structure for the associated region on chromosome 20p12.3/BMP2 locus

The top half of the figure has physical position along the x axis, and the −log₁₀ of the meta-analysis p-value on the y-axis. Each dot on the plot represents the result for one SNP. The bottom half of the figure shows pairwise linkage disequilibrium (LD) for the genotyped SNPs across the region. LD was measured as r² and calculated using the control individuals from the WHI, PLCO and DALS samples recruited from 53 centers across the USA. Darker shading indicates higher levels of LD. The lines between the top and bottom half of the figure connecting the same SNPs.

Figure 2. Genetic variants associated with different cancer sites in the TERT-CLPTM1L region, including the new finding for colorectal cancer for rs2853668

This figure shows the genomic region on chromosome 5.p.15.33 including the two genes TERT and CLPTM1L. The top of the figure shows the genes with each exon represented by a short vertical line. The line below the genes shows the location of the different SNPs that have been associated with various cancer sites relative to the position of the genes (for instance, the first two SNPs are located in the last intron of TERT). The triangle shows the pairwise linkage disequilibrium (LD) of the SNPs. LD was measured as r² and calculated using the control individuals from the WHI, PLCO and DALS samples recruited from 53 centers across the USA. Darker shading indicates higher levels of LD.