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Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

Abstract

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10−10 and rs6687758, OR = 1.09, P = 2.27 × 10−9), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10−8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10−10 and rs7136702, OR = 1.06, P = 4.02 × 10−8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10−10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.

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Figure 1
Figure 2: Forest plots of effect size and direction for the six SNPs associated with CRC.
Figure 3: Regional plots.

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Acknowledgements

Cancer Research UK provided principal funding for this study individually to I.P.M.T., M.G.D., R.S.H., P.P. and J. Cheadle. Additional funding was provided by the Oxford Comprehensive Biomedical Research Centre (to E. Domingo and I.P.M.T.) and the EU FP7 CHIBCHA grant (to L.G.C.-C. and I.P.M.T.). Core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford was provided by grant 075491/Z/04. We are grateful to many colleagues within UK Clinical Genetics Departments (for CORGI) and to many collaborators who participated in the VICTOR and QUASAR2 trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG). Additional funding (to M.G.D.) was provided by the Medical Research Council (G0000657-53203), CORE and Scottish Executive Chief Scientist's Office (K/OPR/2/2/D333, CZB/4/449). We (Edinburgh) gratefully acknowledge the work of the COGS and SOCCS administrative teams; R. Cetnarskyj and the research nurse teams, who all recruited subjects to the studies; the Wellcome Trust Clinical Research Facility for sample preparation; and to all clinicians and pathologists throughout Scotland at the collaborating centres. E.T. was funded by a Cancer Research UK Fellowship (C31250/A10107). The study used the biological and data resources of Generation Scotland. COIN and COINB were funded by the UK Medical Research Council. COIN sample analysis (J. Cheadle) was also funded by Cancer Research Wales, Tenovus and Wales Gene Park. For the Helsinki study, the work was supported by grants from Academy of Finland (Finnish Centre of Excellence Program 2006-2011), the Finnish Cancer Society and the Sigrid Juselius Foundation. For the Cambridge study, we thank the SEARCH study team and all the participants in the study. P.P. is a Cancer Research UK Senior Clinical Research Fellow. This study made use of genotyping data from the 1958 Birth Cohort and NBS samples, kindly made available by the Wellcome Trust Case Control Consortium 2. A full list of the investigators who contributed to the generation of the data is available at http://www.wtccc.org.uk/. Finally, we would like to thank all individuals who participated in the study.

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Contributions

The study was designed and financial support was obtained by R.S.H., I.P.M.T., M.G.D. and H.C. The manuscript was drafted by I.P.M.T., R.S.H. and M.G.D. Statistical and bioinformatic analyses were conducted by S.E.D., S.L.S. and A.T., with contributions from I.P.M.T., J.-B.C. and R.S.H.

Oxford and local collaborators: subject recruitment and sample acquisition were done by E.B., M.G., L.M., A.M.L., D.G.R.E., E.R.M., H.J.W.T. and members of the CORGI Consortium, and by R. Mager, R. Midgley, E.J. and D.J.K. Sample preparation was performed by K.H., S.L.S. and E.E.M.J. Genotyping was performed and coordinated by L.G.C.-C., K.H., A.M.J., M.C., E.E.M.J., A.W. and E. Domingo. A.D. and E. Dermitzakis supplied eQTL data.

Institute of Cancer Research and local collaborators: subject recruitment and sample acquisition to NSCCG were undertaken by S.P. The coordination of sample preparation and genotyping was performed by P.B. Sample preparation and genotyping were performed by A.M.P. and B.O.

Colon Cancer Genetics Group, Edinburgh and local collaborators: subject recruitment and sample acquisition were performed by S.F. and members of the SOCCS and COGS study teams. Sample preparation was coordinated by S.F. Genotyping was performed and coordinated by S.F., E.T., R.A.B. and M.G.D. J.G.D.P. performed the bioinformatic analyses.

The following authors from collaborating groups conceived the local or national study, undertook assembly of case-control series in their respective regions, collected data and samples and variously undertook genotyping and analysis: C.G.S., J. Colley, S.I., T.M. and J. Cheadle in Cardiff; I.N., S.T. and L.A.A. in Finland; and P.P. in Cambridge. All other authors undertook sample collection and phenotype data collection and collation in the respective centers.

Corresponding authors

Correspondence to Richard S Houlston, Malcolm G Dunlop or Ian P M Tomlinson.

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The authors declare no competing financial interests.

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A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

A full list of members is provided in the Supplementary Note.

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Supplementary Tables 1 and 2, Supplementary Figures 1–3 and Supplementary Note (PDF 320 kb)

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Houlston, R., Cheadle, J., Dobbins, S. et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet 42, 973–977 (2010). https://doi.org/10.1038/ng.670

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