title: 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.
abstract: 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.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Webb
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Rudd
authors.forename: Gabrielle S
authors.initials: GS
authors.lastname: Sellick
authors.forename: Rachid
authors.initials: R
authors.lastname: El Galta
authors.forename: Lara
authors.initials: L
authors.lastname: Bethke
authors.forename: Wendy
authors.initials: W
authors.lastname: Wood
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
authors.forename: Steven
authors.initials: S
authors.lastname: Penegar
authors.forename: Laura
authors.initials: L
authors.lastname: Withey
authors.forename: Mobshra
authors.initials: M
authors.lastname: Qureshi
authors.forename: Nichola
authors.initials: N
authors.lastname: Johnson
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.forename: Richard
authors.initials: R
authors.lastname: Gray
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D006113:United Kingdom