A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21

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Abstract

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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Figure 1: Schematic view of association and LD results from panel A in the region on chromosome 8q24.21.

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Acknowledgements

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.

Author information

A complete list of members of the CORGI Consortium is given in the Supplementary Note online. R. Houlston and I.T. designed the study and obtained financial support. Additional authors contributed as follows: Z.K., S.S., S.P. supervision of patient recruitment; G.S., J.P., R.G., S.S., L.M., R. Hubner M.G. and W.W., sample collection; S.P., Z.K., M.G., S.L., S.F., R.W., P.B. and I.C., sample preparation; W.A., A.S., D.K., H.T. and members of the CORGI consortium (available on request), sample acquisition and provision; L.C.-C. and P.B., coordination of genotyping; L.C.-C., E.J., A.R., S.S. and K.H., genotyping; E.W. and J.-B.C., data manipulation and statistical analyses; A.R., expression studies and O.S., 8q amplicon analysis. R. Houlston and I.T. drafted the manuscript with substantial contributions from E.W. All authors contributed to the final paper.

Correspondence to Ian Tomlinson or Richard Houlston.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Tables 1–3 and Supplementary Figure 1 (PDF 232 kb)

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