A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.
Tomlinson I., Webb E., Carvajal-Carmona L., Broderick P., Kemp Z., Spain S., Penegar S., Chandler I., Gorman M., Wood W., Barclay E., Lubbe S., Martin L., Sellick G., Jaeger E., Hubner R., Wild R., Rowan A., Fielding S., Howarth K., CORGI Consortium None., Silver A., Atkin W., Muir K., Logan R., Kerr D., Johnstone E., Sieber O., Gray R., Thomas H., Peto J., Cazier JB., Houlston R.
Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP (P = 1.72 x 10(-7), allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 x 10(-14) (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16-1.39) and 1.47 (95% c.i.: 1.34-1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10-1.34; P = 6.89 x 10(-5)). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.