A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

Ian P M Tomlinson, Emily Webb, Luis Carvajal-Carmona, Peter Broderick, Kimberley Howarth, Alan M. Pittman, Sarah Spain, Steven Lubbe, Axel Walther, Kate Sullivan, Emma Jaeger, Sarah Fielding, Andrew Rowan, Jayaram Vijayakrishnan, Enric Domingo, Ian Chandler, Zoe Kemp, Mobshra Qureshi, Susan M. Farrington, Albert TenesaJames G D Prendergast, Rebecca A. Barnetson, Steven Penegar, Ella Barclay, Wendy Wood, Lynn Martin, Maggie Gorman, Huw Thomas, Julian Peto, D. Timothy Bishop, Richard Gray, Eamonn R. Maher, Anneke Lucassen, David Kerr, D. Gareth R Evans, Clemens Schafmayer, Stephan Buch, Henry Völzke, Jochen Hampe, Stefan Schreiber, Ulrich John, Thibaud Koessler, Paul Pharoah, Tom Van Wezel, Hans Morreau, Juul T. Wijnen, John L. Hopper, Melissa C. Southey, Graham G. Giles, Gianluca Severi, Sergi Castellví-Bel, Clara Ruiz-Ponte, Angel Carracedo, Antoni Castells, Asta Försti, Kari Hemminki, Pavel Vodicka, Alessio Naccarati, Lara Lipton, Judy W C Ho, K. K. Cheng, Pak C. Sham, J. Luk, Jose A G Agúndez, Jose M. Ladero, Miguel De La Hoya, Trinidad Caldés, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri Aaltonen, Jean Baptiste Cazier, Harry Campbell, Malcolm G. Dunlop, Richard S. Houlston

Research output: Contribution to journalArticle

444 Scopus citations

Abstract

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10-4 in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 × 10 -13 overall; P = 6.9 × 10-12 replication), and rs16892766, at 8q23.3 (P = 3.3 × 10-18 overall; P = 9.6 × 10-17 replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

Original languageEnglish (US)
Pages (from-to)623-630
Number of pages8
JournalNature Genetics
Volume40
Issue number5
DOIs
StatePublished - May 2008
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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    Tomlinson, I. P. M., Webb, E., Carvajal-Carmona, L., Broderick, P., Howarth, K., Pittman, A. M., Spain, S., Lubbe, S., Walther, A., Sullivan, K., Jaeger, E., Fielding, S., Rowan, A., Vijayakrishnan, J., Domingo, E., Chandler, I., Kemp, Z., Qureshi, M., Farrington, S. M., ... Houlston, R. S. (2008). A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nature Genetics, 40(5), 623-630. https://doi.org/10.1038/ng.111