Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

Abstract

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10⁻¹⁰ and rs6687758, OR = 1.09, P = 2.27 × 10⁻⁹, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10⁻⁸), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10⁻¹⁰ and rs7136702, OR = 1.06, P = 4.02 × 10⁻⁸) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10⁻¹⁰). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

Figure 1. Overall study design

Figure 2. Forest plots of effect size and direction for the six SNPs associated with CRC.

Boxes denote allelic OR point estimates, their areas being proportional to the inverse variance weight of the estimate. Horizontal lines represent 95% confidence intervals. The diamond (and broken line) represents the summary OR computed under a fixed effects model, with 95% confidence interval given by its width. The unbroken vertical line is at the null value (OR=1.0).

Figure 3. Maps of the (a) 1q41, (b) 3q26.2, (c) 12q13.13 and (d) 20q13.33 regions, showing evidence of association with CRC and local LD structure.

In the association plot, each point represents a SNP genotyped at this locus. For each SNP at the position (kb) shown on the x-axis, -log₁₀P from the allelic association test is indicated on the y-axis. Recombination rate is shown in blue. The SNP with the strongest association in each region is shown as a red diamond. Data were derived from the combined analysis of VQ58, UK1, Scotland1, UK2 and Scotland2; this resulted in relatively few SNPs being shown for each region, but illustrates the rationale for the selection of SNPs for genotyping in the validation sample sets. In the LD plots (lower), derived from HapMap CEU individuals in Haploview. the colour intensity of each SNP represents the strength of LD according to the standard Haploview scheme for r^{2 (}black >0.90 through shades of grey to white 0.0 ). Note that DUSP10 is not shown for chromosome 1q41 but maps to 219,941,389-219,982,084; similarly, TERC is not shown for chromosome 3q26.2, but lies at 170,965,092-170,965,542. Physical positions are based on NCBI build 36 of the human genome.