A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

Abstract

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.

Figure 1. Genome-wide P-values (–log₁₀P, y-axis) plotted against their respective chromosomal positions (x-axis).

Known regions attaining genome-wide significance (i.e. P = 5.0 × 10⁻⁸) are labelled with their chromosomal location. Variants in grey lie in novel regions that reach the significance threshold level (P = 1.0 × 10⁻⁷) required for variants to be analysed further in this study. Variants in black lie in novel regions attaining genome-wide significance.

Figure 2. Forest plot of the odds ratios for the association between rs72647484, rs16941835, rs10904849 and CRC.

Studies were weighted according to the inverse of the variance of the log of the OR calculated by unconditional logistic regression. Horizontal lines: 95% confidence intervals (95% CI). Box: OR point estimate; its area is proportional to the weight of the study. Diamond (and broken line): overall summary estimate, with confidence interval given by its width. Unbroken vertical line: null value (OR = 1.0).

Figure 3

Regional plot of association results and recombination rates for the (a) 1p36.12, (b) 10p13 and (c) 16q24.1 risk loci. Association results of both genotyped (triangles) and imputed (circles) SNPs in the GWAS samples and recombination rates within the loci at 1p36.12 (a), 10p13 (b) and 16q24 (c). For each plot, −log₁₀ P values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The top imputed SNP in each combined analysis is shown as a large triangle and is labelled by its rsID. The colour intensity of each symbol reflects the extent of LD with the top SNP: white (r² = 0) through to dark red (r² = 1.0), with r² estimated from the 1000 Genomes Phase 1 data. Genetic recombination rates (cM/Mb), are shown with a light blue line. Physical positions are based on NCBI build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to each region of association. The lower panel shows the chromatin state segmentation track (ChromHMM).