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

Nature Geneticsvolume 39, pages984–988 (2007)Cite this article

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, providingP = 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.

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Author notes

  1. Emily Webb, Luis Carvajal-Carmona, Peter Broderick, Zoe Kemp and Sarah Spain: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular and Population Genetics Laboratory, Cancer Research UK, London, WC2A 3PX, UK

    Ian Tomlinson, Luis Carvajal-Carmona, Zoe Kemp, Sarah Spain, Maggie Gorman, Ella Barclay, Lynn Martin, Emma Jaeger, Andrew Rowan & Kimberley Howarth

  2. Institute of Cancer, Bart's and the London Medical School, Queen Mary College, University of London, UK

    Ian Tomlinson & Andrew Silver

  3. Section of Cancer Genetics, Institute of Cancer Research, Sutton, SM2 5NG, UK

    Emily Webb, Peter Broderick, Steven Penegar, Ian Chandler, Wendy Wood, Steven Lubbe, Gabrielle Sellick, Richard Hubner, Ruth Wild, Sarah Fielding & Richard Houlston

  4. Colorectal Cancer Unit, Cancer Research UK, St Mark's Hospital, Harrow, HA1 3UJ, UK

    Wendy Atkin

  5. Division of Epidemiology and Public Health, University of Nottingham, Medical School, Queen's Medical Centre, Nottingham, NG7 2UH, UK

    Kenneth Muir & Richard Logan

  6. Department of Clinical Pharmacology, Oxford University, Radcliffe Infirmary, Oxford, OX2 6HA, UK

    David Kerr & Elaine Johnstone

  7. Cancer and Immunogenetics Laboratory, Weatherall Institute for Molecular Medicine, Oxford University, Oxford, OX3 9DS, UK

    Oliver Sieber

  8. Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, B15 2RR, UK

    Richard Gray

  9. Family Cancer Clinic, Cancer Research UK, St Mark's Hospital, Harrow, HA1 3UJ, UK

    Huw Thomas

  10. Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK

    Julian Peto

  11. Section of Epidemiology, Institute of Cancer Research, Surrey, SM2 5NG, UK

    Julian Peto

  12. Bioinformatics and Biostatistics, Cancer Research UK, London, WC2A 3PX, UK

    Jean-Baptiste Cazier

Authors
  1. Ian Tomlinson

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  2. Emily Webb

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  3. Luis Carvajal-Carmona

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  4. Peter Broderick

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  5. Zoe Kemp

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  6. Sarah Spain

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  7. Steven Penegar

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  8. Ian Chandler

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  9. Maggie Gorman

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  10. Wendy Wood

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  11. Ella Barclay

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  12. Steven Lubbe

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  13. Lynn Martin

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  14. Gabrielle Sellick

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  15. Emma Jaeger

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  16. Richard Hubner

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  17. Ruth Wild

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  18. Andrew Rowan

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  19. Sarah Fielding

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  20. Kimberley Howarth

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  21. Andrew Silver

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  22. Wendy Atkin

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  23. Kenneth Muir

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  24. Richard Logan

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  25. David Kerr

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  26. Elaine Johnstone

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  27. Oliver Sieber

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  28. Richard Gray

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  29. Huw Thomas

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  30. Julian Peto

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  31. Jean-Baptiste Cazier

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  32. Richard Houlston

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Consortia

the CORGI Consortium

Contributions

A complete list of members of the CORGI Consortium is given in theSupplementary 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.

Corresponding authors

Correspondence toIan Tomlinson orRichard Houlston.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

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Tomlinson, I., Webb, E., Carvajal-Carmona, L.et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.Nat Genet39, 984–988 (2007). https://doi.org/10.1038/ng2085

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