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Human Molecular Genetics Advance Access originally published online on September 25, 2006
Human Molecular Genetics 2006 15(21):3263-3271; doi:10.1093/hmg/ddl401
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives

Emily L. Webb1,{dagger}, Matthew F. Rudd1,{dagger}, Gabrielle S. Sellick1, Rachid El Galta1, Lara Bethke1, Wendy Wood1, Olivia Fletcher2, Steven Penegar1, Laura Withey1, Mobshra Qureshi1, Nichola Johnson2, Ian Tomlinson3, Richard Gray4, Julian Peto2,5 and Richard S. Houlston1,*

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 and 5 Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, UK

* To whom correspondence should be addressed at: Section of Cancer Genetics, Brookes Lawley Building, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK. Tel: +44 2087224175; Fax: +44 2087224359; Email: richard.houlston{at}icr.ac.uk

Received August 8, 2006; Accepted September 20, 2006

To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 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% confidence interval (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 publicly 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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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