Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis

Abstract

To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10(-11)]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10(-10)) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10(-8)). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC.

Figure 1.

Forest plot of the ORs for the association between CRC and rs1035209. Studies were weighted according to the inverse of the variance of the log of the OR calculated by unconditional logistic regression. Horizontal lines: 95% CI. Box: OR point estimate; its area is proportional to the weight of the study. Diamond (and broken line): overall summary estimate, with CI given by its width. Unbroken vertical line: null value (OR = 1.0).

Figure 2.

Regional plots of association results, recombination rates and chromatin state segmentation track for (A) 10q24.2, (B) 12p13.32 and (C) 1q25.3 susceptibility loci. Association results of both genotyped (triangles) and imputed (circles) SNPs in the GWAS samples and recombination rates for rates. −log₁₀ P-values (y axis) of the SNPs are shown according to their chromosomal positions (x axis). The top genotyped SNP in each combined analysis is shown as a large triangle and is labelled by its rsID. Colour intensity of each symbol reflects the extent of LD with the top genotyped SNP; white (r² = 0) through to dark red (r² = 1.0) Genetic recombination rates, estimated using HapMap Utah residents of Western and Northern European ancestry (CEU) samples, 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 the region of association. Genes have been redrawn to show the relative positions; therefore, maps are not to physical scale. The lower panel shows the chromatin state segmentation track (ChromHMM).

Figure 3.

Forest plot of the ORs for associations between CRC and (A) rs3217810 and (B) rs10911251. Studies were weighted according to the inverse of the variance of the log of the OR calculated by unconditional logistic regression. Horizontal lines: 95% CI. Box: OR point estimate; its area is proportional to the weight of the study. Diamond (and broken line): overall summary estimate, with CI given by its width. Unbroken vertical line: null value (OR = 1.0). Summary estimates are shown for studies from Peters et al., from the three GWAS not included in that study and a combined estimate.