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Human Molecular Genetics Advance Access published online on September 25, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl401
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received August 8, 2006
Revised September 20, 2006
Accepted September 20, 2006

Article

Search for low penetrance alleles for colorectal cancer through a scan of 1,467 non-synonymous SNPs in 2,575 cases and 2,707 controls with validation by kin-cohort analysis of 14,704 first-degree relatives

Emily L Webb 1, Matthew F Rudd 1, Gabrielle S Sellick 1, Rachid El Galta 1, Lara Bethke 1, Wendy Wood 1, Olivia Fletcher 2, Stephen Penegar 1, Laura Withey 1, Mobshra Qureshi 1, Nichola Johnson 2, Ian Tomlinson 3, Richard Gray 4, Julian Peto 5, and Richard S Houlston 6 *

1 Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK
2 The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK
3 Molecular and Population Genetics Laboratory, Cancer Research UK, London, UK
4 Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK
5 Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK; and Institute of Cancer Research, Surrey, UK
6 Section of Cancer Genetics, Brookes Lawley Building, Institute of Cancer Research, Sutton, Surrey, SM2 5NG, UK

* To whom correspondence should be addressed.
Richard S Houlston, E-mail: Richard.Houlston{at}icr.ac.uk


  Abstract

To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1,467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2,575 cases and 2,707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP, AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L (OR = 1.48; 95% CI: 1.06-2.07) and P1054R (OR = 1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95%CI: 0.69-0.97). To validate associations we performed a kin-cohort analysis on the 14,704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publically available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses.


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