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Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

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Abstract

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 × 10−10), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 × 10−26) and 18q21 (rs4939827; OR = 1.2; P = 7.8 × 10−28). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75–3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.

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Figure 1: Fine mapping of the 8q24 and 18q23 (SMAD7) loci.
Figure 2: Forest plot of effect size and direction for each of the three SNPs associated with CRC (rs7014346, rs4939827 and rs3802842).

Change history

  • 13 April 2008

    In the version of this article initially published online, one of the co-authors (Kimberley Howarth) was inadvertently omitted from the author list. Her name should have been listed immediately after Zoe Kemp, with affiliation 18. This error has been corrected in all versions of the article.

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Acknowledgements

Edinburgh: We are grateful to all participants in these studies and to nursing and administrative staff on the COGS and SOCCS studies. We acknowledge the working arrangements with the Genotyping Core at the Wellcome Trust Clinical Research Facility, managed by L. Murphy, for sample preparations and genotyping (COGS, SOCCS, Scotland replication and LBC 1936 samples). We also thank departments in central Scottish NHS, including Cancer Registry, Scottish Cancer Intelligence Unit of ISD and the Family Practitioner Committee for population control recruitment. The work was funded by grants from Cancer Research UK (C348/A3758 and A8896, C48/A6361), Medical Research Council (G0000657-53203) and Scottish Executive Chief Scientist's Office (K/OPR/2/2/D333, CZB/4/449), and a Centre Grant from CORE as part of the Digestive Cancer Campaign. J.P. was funded by an MRC PhD studentship. Research work at the Edinburgh Parallel Computing Centre was supported by the Scottish Funding Council through the 'e-Science Data, Information and Knowledge Transformation 2' (eDIKT2) project (SFC grant HR04019). The Lothian Birth Cohort 1936 phenotype and DNA collection was supported by Programme Grant number 251 and the Sidney De Haan Research Award from Research Into Ageing, and by the Disconnected Mind Award from Help the Aged. I.J.D. holds a Royal Society-Wolfson Research Merit Award. Sample collection, DNA extraction and phenotype data were collected at the Wellcome Trust Clinical Research Facility, Edinburgh. Cambridge: We thank the SEARCH study team and all the participants in the study. P.D.P.P. is a Cancer Research UK Senior Clinical Research Fellow. T.K. is funded by the Foundation Dr Henri Dubois-Ferriere Dinu Lipatti. Kiel: The study was supported by the German National Genome Research Network (NGFN) through the POPGEN biobank (BmBF 01GR0468) and the National Genotyping Platform. Further support was obtained through the MediGrid and Services@MediGrid projects (01AK803G and 01IG07015B). SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant no. ZZ9603), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Heidelberg: We wish to thank all participants and the staff of the participating clinics for their contribution to the data collection and B.Kaspereit, K. Smit and U. Eilber in the Division of Cancer Epidemiology, and U. Handte-Daub, S. Toth and B. Collins in the Division of Clinical Epidemiology and Aging Research, German Cancer Research Center for their excellent technical assistance. This study was supported by the German Research Council (Deutsche Forschungsgemeinschaft), grant numbers BR 1704/6-1, BR 1704/6-3 and CH 117/1-1, and by the German Federal Ministry for Education and Research, grant number 01 KH 0404. Barcelona: The Bellvitge Colorectal Cancer Study has been funded by the Spanish Instituto de Salud Carlos III, FIS (grants 97/0787, 03/0114 and 05/1006), Ministry of Science and Education (SAF 06/06084) and Acción Transversal del Cáncer 2008. London: We acknowledge Cancer Research UK Research funding and thank all those who participated in this study. Michigan: Genotyping of Michigan samples was supported by NCI R01 CA81488, the Irving Weinstein Foundation and the University of Michigan Comprehensive Cancer Center Core Grant, P30 CA46592. Tokyo: We thank members of the Rotary Club of Osaka Midosuji District (Japan) for collecting samples, and M. Kubo (RIKEN, Japan) for SNP genotyping. The study was supported by 'Biobank Japan', a project working toward personalized medicine. Canada: We gratefully acknowledge the contribution of A. Belisle, V. Catudal and R. Fréchette. Cancer Care Ontario, as the host organization to the ARCTIC Genome Project, acknowledges that this project was funded by Genome Canada through the Ontario Genomics Institute, by Génome Québec, the Ministère du Dévelopement Économique et Régional et de la Recherche du Québec and the Ontario Institute for Cancer Research (B.W.Z., T.J.H., C.M.T.G. and S.G.). Additional funding was provided by the National Cancer Institute of Canada (NCIC) through the Cancer Risk Assessment (CaRE) Program Project Grant. The work was supported through collaboration and cooperative agreements with the Colon Cancer Family Registry and PIs, supported by the National Cancer Institute, National Institutes of Health under RFA CA-95-011, including the Ontario Registry for Studies of Familial Colorectal Cancer (S.G.) (U01 CA076783). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating institutions or investigators in the Colon CFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the Colon CFR.

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Contributions

M.G.D. conceived of the study; A.T., S.M.F., H.C. and M.G.D. designed it; A.T., S.M.F., H.C. and M.G.D. wrote the paper with input from other authors; A.T., S.M.F., J.G.D.P. and C. Semple undertook data manipulations, statistical analysis and bioinformatic interrogations; S.M.F., M.W., N.H., R.A.B., A.J.C. undertook various aspects of laboratory analysis; M.E.P., E.T., R.C., N.C. and A.J.C. coordinated and/or undertook recruitment, collected phenotype data, undertook related data handling and curation, managed recruitment, obtained biological samples; F.J.L.R., L.A.S. and K.K. contributed to writing code in EPCC and parallelized the analysis for permutation testing. The following authors from the various collaborating groups conceived the local study, undertook assembly of case/control series in their respective regions, collected data and samples, variously undertook genotyping and analysis: T. Koessler and P.D.P.P. in Cambridge; S.B., C. Schafmayer, J.T., S.S., H.V., C.O.S. and J.H. in Kiel; J.C.-C., M.H. and H.B. in Heidelberg; S.W. and F.C. in Heidelberg; G.C. and V.M. in Barcelona; I.J.D. and J.M.S. in Edinburgh; I.P.M.T., Z.K. and L.C.-C. in London LRF; E.W., P.B., J.V. and R.S.H. in London ICR; G.R., D.B., L.R., S.B.G. in Michigan/Haifa; K.M., T. Kidokoro and Y.N. in Tokyo; B.W.Z., C.M.T.G., J.R., R.K., A.M., T.J.H. and S.G. in Toronto and Quebec. All undertook sample collection and phenotype data collection and collation in the respective centres. M.G.D., H.C., I.P.M.T. and R.S.H. obtained funding for the study.

Corresponding author

Correspondence to Malcolm G Dunlop.

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Competing interests

Dennis Ballinger is employed by Perlegen Sciences, which undertakes whole genome genetic analysis commercially. Brent Zanke is founder and equity holder of Arctic Dx, a new Canadian biotechnology company that has received a license in the field of diagnostics for intellectual property generated by several institutions in Canada and other countries.

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Supplementary Methods, Supplementary Note, Supplementary Figures 1–9, Supplementary Tables 1–7 (PDF 2045 kb)

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Tenesa, A., Farrington, S., Prendergast, J. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet 40, 631–637 (2008). https://doi.org/10.1038/ng.133

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