Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk

Abstract

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.

Figure 1. Forest plots for risk variants in the six newly identified loci

The six plots represent (a) rs704017, (b) rs11196172, (c) rs174537, (d) rs10849432, (e) rs12603526 and (f) rs1800469. Per-allele ORs are presented, with the area of each box proportional to the inverse variance weight of the estimate. Horizontal lines represent 95% CIs. Diamonds represent summary ORs generated under a fixed-effects meta-analysis; width of the diamonds corresponds to the 95% CIs. Unbroken vertical lines represent the null value; broken vertical lines represent the summary ORs for all studies for each SNP.

Figure 2. Association of selected risk variants identified in this study with gene expression in colon tumor tissue

The three plots are for (a) rs11196172 and TCF7L2, (b) rs11196172 and VTI1A, and (c) rs1535 and FADS2. Gene expression levels are represented by per kilobase of exon per million mapped reads (RPKM) value based on the three genotypes of each SNP in red, blue and green. The median RPKM values and the interquartile range for each SNP are presented in the overlaid box plot. In (a) and (b), RPKM values are shown at normal scale, whereas RPKM values in (c) are shown with a log scale due to departure from normal distribution.