Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Abstract

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10^-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r² = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

Figure 1.

Forest plot of the odds ratios for the association between rs992157 and CRC. Studies were weighted according to the inverse of the variance of the log of the OR. Horizontal lines: 95% confidence intervals (95% CI). Box: OR point estimate; its area is proportional to the weight of the study. Diamond: overall summary estimate, with confidence interval given by its width. Vertical line: null value (OR = 1.0).

Figure 2.

Regional plot of association results and recombination rates for the 2q35 locus. In the panel, −log₁₀ P values (y-axis) of the SNPs are shown according to their chromosomal positions (x-axis). The top SNP 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) in HCT116 CRC and GM12878 lymphoblastoid cell lines.

Figure 3.

Quantile–quantile (Q–Q) plot of observed and expected CRC association P-values for 200 IBD risk SNPs (15, 16).

Figure 4.

Hive plot of common protein–protein interactions between CRC and IBD defined by risk SNPs. Each arc represents an interaction between two proteins, and the distance from the centre of the plot corresponds to a greater number of protein–protein interactions (higher degree of the node). The left arm represents proteins that were only identified using the CRC SNPs, the right arm represents proteins that were only identified using the IBD SNPs, and the central arm represents the common proteins, highlighting the previously associated tag genes.