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 × 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 × 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 × 10−5). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.
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We thank all the affected and control individuals for their participation, and we thank C. Thirlwell, K. Monahan, A. Walther, J. Harvey, H. Schaschl, C. Cummings, E Volikos, G. Clark and colleagues. This work was principally supported by a grant from Cancer Research UK. Additional grant support was provided by CORE, the European Union (CCPRB LSHC-CT-2004-503465), the Bobby Moore Fund and the Thomas Falknor Fund. P.B. and G.S. are funded by Leukaemia Research. R. Hubner is in receipt of a Clinical Training Fellowship from Cancer Research UK.
The authors declare no competing financial interests.
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