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

Richard S. Houlston; Emily Webb; Peter Broderick; Alan M. Pittman; Maria Chiara Di Bernardo; Steven Lubbe; Ian Chandler; Jayaram Vijayakrishnan; Kate Sullivan; Steven Penegar; Luis Carvajal-Carmona; Kimberley Howarth; Emma Jaeger; Sarah L. Spain; Axel Walther; Ella Barclay; Lynn Martin; Maggie Gorman; Enric Domingo; Ana S. Teixeira; David Kerr; Jean Baptiste Cazier; Iina Niittymäki; Sari Tuupanen; Auli Karhu; Lauri A. Aaltonen; Ian P M Tomlinson; Susan M. Farrington; Albert Tenesa; James G D Prendergast; Rebecca A. Barnetson; Roseanne Cetnarskyj; Mary E. Porteous; Paul D P Pharoah; Thibaud Koessler; Jochen Hampe; Stephan Buch; Clemens Schafmayer; Jurgen Tepel; Stefan Schreiber; Henry Völzke; Jenny Chang-Claude; Michael Hoffmeister; Hermann Brenner; Brent W. Zanke; Alexandre Montpetit; Thomas J. Hudson; Steven Gallinger; Harry Campbell; Malcolm G. Dunlop

doi:10.1038/ng.262

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

Richard S. Houlston, Emily Webb, Peter Broderick, Alan M. Pittman, Maria Chiara Di Bernardo, Steven Lubbe, Ian Chandler, Jayaram Vijayakrishnan, Kate Sullivan, Steven Penegar, Luis Carvajal-Carmona, Kimberley Howarth, Emma Jaeger, Sarah L. Spain, Axel Walther, Ella Barclay, Lynn Martin, Maggie Gorman, Enric Domingo, Ana S. TeixeiraDavid Kerr, Jean Baptiste Cazier, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri A. Aaltonen, Ian P M Tomlinson, Susan M. Farrington, Albert Tenesa, James G D Prendergast, Rebecca A. Barnetson, Roseanne Cetnarskyj, Mary E. Porteous, Paul D P Pharoah, Thibaud Koessler, Jochen Hampe, Stephan Buch, Clemens Schafmayer, Jurgen Tepel, Stefan Schreiber, Henry Völzke, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Brent W. Zanke, Alexandre Montpetit, Thomas J. Hudson, Steven Gallinger, Harry Campbell, Malcolm G. Dunlop

Neurology

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	1426-1435
Number of pages	10
Journal	Nature Genetics
Volume	40
Issue number	12
DOIs	https://doi.org/10.1038/ng.262
State	Published - Dec 2008

ASJC Scopus subject areas

Genetics

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Houlston, R. S., Webb, E., Broderick, P., Pittman, A. M., Di Bernardo, M. C., Lubbe, S., Chandler, I., Vijayakrishnan, J., Sullivan, K., Penegar, S., Carvajal-Carmona, L., Howarth, K., Jaeger, E., Spain, S. L., Walther, A., Barclay, E., Martin, L., Gorman, M., Domingo, E., ... Dunlop, M. G. (2008). Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nature Genetics, 40(12), 1426-1435. https://doi.org/10.1038/ng.262

Houlston, Richard S. ; Webb, Emily ; Broderick, Peter ; Pittman, Alan M. ; Di Bernardo, Maria Chiara ; Lubbe, Steven ; Chandler, Ian ; Vijayakrishnan, Jayaram ; Sullivan, Kate ; Penegar, Steven ; Carvajal-Carmona, Luis ; Howarth, Kimberley ; Jaeger, Emma ; Spain, Sarah L. ; Walther, Axel ; Barclay, Ella ; Martin, Lynn ; Gorman, Maggie ; Domingo, Enric ; Teixeira, Ana S. ; Kerr, David ; Cazier, Jean Baptiste ; Niittymäki, Iina ; Tuupanen, Sari ; Karhu, Auli ; Aaltonen, Lauri A. ; Tomlinson, Ian P M ; Farrington, Susan M. ; Tenesa, Albert ; Prendergast, James G D ; Barnetson, Rebecca A. ; Cetnarskyj, Roseanne ; Porteous, Mary E. ; Pharoah, Paul D P ; Koessler, Thibaud ; Hampe, Jochen ; Buch, Stephan ; Schafmayer, Clemens ; Tepel, Jurgen ; Schreiber, Stefan ; Völzke, Henry ; Chang-Claude, Jenny ; Hoffmeister, Michael ; Brenner, Hermann ; Zanke, Brent W. ; Montpetit, Alexandre ; Hudson, Thomas J. ; Gallinger, Steven ; Campbell, Harry ; Dunlop, Malcolm G. / Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. In: Nature Genetics. 2008 ; Vol. 40, No. 12. pp. 1426-1435.

@article{a095f9ed8d384a819b2f3127dd9b19cd,

title = "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.",

author = "Houlston, {Richard S.} and Emily Webb and Peter Broderick and Pittman, {Alan M.} and {Di Bernardo}, {Maria Chiara} and Steven Lubbe and Ian Chandler and Jayaram Vijayakrishnan and Kate Sullivan and Steven Penegar and Luis Carvajal-Carmona and Kimberley Howarth and Emma Jaeger and Spain, {Sarah L.} and Axel Walther and Ella Barclay and Lynn Martin and Maggie Gorman and Enric Domingo and Teixeira, {Ana S.} and David Kerr and Cazier, {Jean Baptiste} and Iina Niittym{\"a}ki and Sari Tuupanen and Auli Karhu and Aaltonen, {Lauri A.} and Tomlinson, {Ian P M} and Farrington, {Susan M.} and Albert Tenesa and Prendergast, {James G D} and Barnetson, {Rebecca A.} and Roseanne Cetnarskyj and Porteous, {Mary E.} and Pharoah, {Paul D P} and Thibaud Koessler and Jochen Hampe and Stephan Buch and Clemens Schafmayer and Jurgen Tepel and Stefan Schreiber and Henry V{\"o}lzke and Jenny Chang-Claude and Michael Hoffmeister and Hermann Brenner and Zanke, {Brent W.} and Alexandre Montpetit and Hudson, {Thomas J.} and Steven Gallinger and Harry Campbell and Dunlop, {Malcolm G.}",

note = "Funding Information: 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{\textquoteright}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{\textquoteright}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 Forschungsgemein-schaft), 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. Fr{\'e}chette. 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 G{\'e}nome Qu{\'e}bec, the Minist{\`e}re du D{\'e}velopement {\'E}conomique et R{\'e}gional et de la Recherche du Qu{\'e}bec 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.",

year = "2008",

month = dec,

doi = "10.1038/ng.262",

language = "English (US)",

volume = "40",

pages = "1426--1435",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "12",

}

Houlston, RS, Webb, E, Broderick, P, Pittman, AM, Di Bernardo, MC, Lubbe, S, Chandler, I, Vijayakrishnan, J, Sullivan, K, Penegar, S, Carvajal-Carmona, L, Howarth, K, Jaeger, E, Spain, SL, Walther, A, Barclay, E, Martin, L, Gorman, M, Domingo, E, Teixeira, AS, Kerr, D, Cazier, JB, Niittymäki, I, Tuupanen, S, Karhu, A, Aaltonen, LA, Tomlinson, IPM, Farrington, SM, Tenesa, A, Prendergast, JGD, Barnetson, RA, Cetnarskyj, R, Porteous, ME, Pharoah, PDP, Koessler, T, Hampe, J, Buch, S, Schafmayer, C, Tepel, J, Schreiber, S, Völzke, H, Chang-Claude, J, Hoffmeister, M, Brenner, H, Zanke, BW, Montpetit, A, Hudson, TJ, Gallinger, S, Campbell, H & Dunlop, MG 2008, 'Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer', Nature Genetics, vol. 40, no. 12, pp. 1426-1435. https://doi.org/10.1038/ng.262

Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. / Houlston, Richard S.; Webb, Emily; Broderick, Peter; Pittman, Alan M.; Di Bernardo, Maria Chiara; Lubbe, Steven; Chandler, Ian; Vijayakrishnan, Jayaram; Sullivan, Kate; Penegar, Steven; Carvajal-Carmona, Luis; Howarth, Kimberley; Jaeger, Emma; Spain, Sarah L.; Walther, Axel; Barclay, Ella; Martin, Lynn; Gorman, Maggie; Domingo, Enric; Teixeira, Ana S.; Kerr, David; Cazier, Jean Baptiste; Niittymäki, Iina; Tuupanen, Sari; Karhu, Auli; Aaltonen, Lauri A.; Tomlinson, Ian P M; Farrington, Susan M.; Tenesa, Albert; Prendergast, James G D; Barnetson, Rebecca A.; Cetnarskyj, Roseanne; Porteous, Mary E.; Pharoah, Paul D P; Koessler, Thibaud; Hampe, Jochen; Buch, Stephan; Schafmayer, Clemens; Tepel, Jurgen; Schreiber, Stefan; Völzke, Henry; Chang-Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; Zanke, Brent W.; Montpetit, Alexandre; Hudson, Thomas J.; Gallinger, Steven; Campbell, Harry; Dunlop, Malcolm G.

In: Nature Genetics, Vol. 40, No. 12, 12.2008, p. 1426-1435.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

AU - Houlston, Richard S.

AU - Webb, Emily

AU - Broderick, Peter

AU - Pittman, Alan M.

AU - Di Bernardo, Maria Chiara

AU - Lubbe, Steven

AU - Chandler, Ian

AU - Vijayakrishnan, Jayaram

AU - Sullivan, Kate

AU - Penegar, Steven

AU - Carvajal-Carmona, Luis

AU - Howarth, Kimberley

AU - Jaeger, Emma

AU - Spain, Sarah L.

AU - Walther, Axel

AU - Barclay, Ella

AU - Martin, Lynn

AU - Gorman, Maggie

AU - Domingo, Enric

AU - Teixeira, Ana S.

AU - Kerr, David

AU - Cazier, Jean Baptiste

AU - Niittymäki, Iina

AU - Tuupanen, Sari

AU - Karhu, Auli

AU - Aaltonen, Lauri A.

AU - Tomlinson, Ian P M

AU - Farrington, Susan M.

AU - Tenesa, Albert

AU - Prendergast, James G D

AU - Barnetson, Rebecca A.

AU - Cetnarskyj, Roseanne

AU - Porteous, Mary E.

AU - Pharoah, Paul D P

AU - Koessler, Thibaud

AU - Hampe, Jochen

AU - Buch, Stephan

AU - Schafmayer, Clemens

AU - Tepel, Jurgen

AU - Schreiber, Stefan

AU - Völzke, Henry

AU - Chang-Claude, Jenny

AU - Hoffmeister, Michael

AU - Brenner, Hermann

AU - Zanke, Brent W.

AU - Montpetit, Alexandre

AU - Hudson, Thomas J.

AU - Gallinger, Steven

AU - Campbell, Harry

AU - Dunlop, Malcolm G.

N1 - Funding Information: 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 Forschungsgemein-schaft), 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.

PY - 2008/12

Y1 - 2008/12

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=56749176944&partnerID=8YFLogxK

U2 - 10.1038/ng.262

DO - 10.1038/ng.262

M3 - Article

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AN - SCOPUS:56749176944

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JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 12

ER -

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

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