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Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

Abstract

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 × 10−10), 16q22.1 (rs9929218, CDH1; P = 1.2 × 10−8), 19q13.1 (rs10411210, RHPN2; P = 4.6 × 10−9) and 20p12.3 (rs961253; P = 2.0 × 10−10). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.

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Figure 1: Regional plots of the four confirmed associations (14q22.2, 16q22.1, 19q13.1 and 20p12.3).
Figure 2: Forest plot of effect size and direction for the four SNPs associated with CRC.
Figure 3: Power of the meta-analysis to identify each of the ten colorectal cancer susceptibility alleles, stipulating a P value of 10−5.

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Acknowledgements

Cancer Research UK provided principal funding for this study (A6360). We would like to thank all individuals that participated in this study.

Institute of Cancer Research: Work was supported by the Bobby Moore Cancer Research UK (C1298/A8362). Additional funding was provided by the European Union (CPRB LSHC-CT-2004-503465) and CORE. I.C. was in receipt of a clinical training fellowship from St George's Hospital Medical School. S.L. was supported by a PhD studentship from Cancer Research UK. We are grateful to colleagues at the UK National Cancer Research Network.

Oxford: Work was supported by CORE and the Bobby Moore Fund. We are grateful to colleagues at UK Clinical Genetics Centres and the UK National Cancer Research Network.

Edinburgh: The work was supported by Cancer Research UK grant numbers C348/A3758 and A8896, C48/A6361 and the Bobby Moore Fund, which supports the work of the Colon Cancer Genetics Group through Cancer Research UK. Additional funding was provided by the Medical Research Council (G0000657-53203), Scottish Executive Chief Scientist's Office (K/OPR/2/2/D333, CZB/4/449), center grant from CORE as part of the Digestive Cancer Campaign. J.P. was funded by an MRC PhD studentship. We gratefully acknowledge the work of the COGS and SOCCS administrative teams; R. Cetnarskyj and the research nurse teams, all who recruited to the studies; the Wellcome Trust Clinical Research Facility for sample preparation; and all clinicians and pathologists throughout Scotland at collaborating centers. The study used the biological and data resource of Generation Scotland.

Finland: This work was supported by grants from Academy of Finland (Finnish Centre of Excellence Program 2006-2011), the Finnish Cancer Society, the Sigrid Juselius Foundation and the European Commission (9LSHG-CT-2004-512142).

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 number. 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, 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.

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. 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.

This study made use of genotyping data on the 1958 Birth Cohort. Genotyping data on controls was generated and generously supplied to us by Panagiotis Deloukas of the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk.

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Contributions

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

Institute of Cancer Research: Subject recruitment and sample acquisition to NSCCG were undertaken by S.P. Coordination of sample preparation and genotyping was performed by P.B. Sample preparation and genotyping performed by A.M.P., K.S., J.V. and S.L. Histology review was by I.C. Testing of MSI was performed by S.L. and I.C.

Wellcome Trust Centre for Human Genetics: Subject recruitment and sample acquisition were undertaken by E.B., M.G., L.M. and members of the CoRGI Consortium and D.K. Sample preparation was performed by K.H., S.L.S. and E.J. Genotyping was performed and co-ordinated by L.C.-C., K.H., A.S.T., S.L.S., A.W., E.J. and E.D.

Colon Cancer Genetics Group, Edinburgh: Study design and funding: M.G.D., H.C., A.T., S.M.F. and M.E.P. Subject recruitment and sample acquisition was led by M.G.D., H.C., M.E.P., R.C., S.M.F. and members of the SOCCS/COGS study teams. Sample preparation was co-ordinated by S.M.F. and R.A.B. Histology review: M.G.D. and S.M.F. Genotyping was performed and co-ordinated by S.M.F. and M.G.D. A.T. performed statistical analyses. J.G.P. performed bioinformatic analyses. 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: I.N., S.T., A.K. and L.A.A. in Finland; T.K. and P.D.P. in Cambridge; S.S., H.V., S.B., C.S., J.T. and J.H. in Kiel; J.C.-C., M.H. and H.B. in Heidelberg; B.W.Z., A.M., T.J.H. and S.G., in Toronto and Montreal. All undertook sample collection and phenotype data collection and collation in the respective centers.

Corresponding authors

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

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

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COGENT Study. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet 40, 1426–1435 (2008). https://doi.org/10.1038/ng.262

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