Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Abstract

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.

Fig. 1

Study design

Fig. 2

Manhattan plot showing all loci containing genetic risk variants independently associated with colorectal cancer risk at P < 5 × 10⁻⁸ in European populations. SNPs on the left of the plot are new SNPs identified in this study, and SNPs on the right were identified in previous studies and replicated at genome-wide significance in this study. The 79 risk SNPs consisted of 31 previously reported SNPs, 39 new risk SNPs, and nine SNPs previously identified in Asian but not in European populations (denoted in dark gold). Dotted lines indicate SNPs that were identified as independent through conditional analysis. Square brackets indicate the position of the sentinel SNP relative to nearest genes (“gene1-[]-gene2” for intergenic SNPs, “[gene]” for intragenic SNPs). The distance from the sentinel SNP to each gene is proportional to the number of dashes. The red line indicates the genome-wide significance threshold. The x-axis represents the −log₁₀P-values of the SNPs, and the y-axis represents the chromosomal positions

Fig. 3

Regional plots of exemplar colorectal cancer risk loci. In the main panel, −log₁₀P-values (y-axis) of the SNPs are shown according to their chromosomal positions (x-axis). 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 EUR 1000 Genomes data. Genetic recombination rates (cM/Mb) are shown with a light blue line. Physical positions are based on GRCh37 of the human genome. Where available, the upper panel shows Hi-C contacts from HT29 or LoVo. The lower panel shows the chromatin state segmentation track from the Roadmap Epigenomics project (colonic mucosa, rectal mucosa, sigmoid colon), and HCT116. Also shown are the relative positions of genes and transcripts mapping to each region of association. a rs12255141 (10q25.2); b rs12979278 (19q13); c rs2735940 (5p15); d rs7398375 (12q13.3)