title: Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13.
abstract: In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Spain
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Howarth
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jones
authors.forename: Zhan
authors.initials: Z
authors.lastname: Su
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: Jennet
authors.initials: J
authors.lastname: Williams
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Paul
authors.initials: P
authors.lastname: Pharoah
authors.forename: David J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: Jeremy
authors.initials: J
authors.lastname: Cheadle
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.forename: Oliver
authors.initials: O
authors.lastname: Sieber
authors.forename: Lara
authors.initials: L
authors.lastname: Lipton
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Clara
authors.initials: C
authors.lastname: Ruiz-Ponte
authors.forename: Ceres
authors.initials: C
authors.lastname: Fernandez-Rozadilla
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Antoni
authors.initials: A
authors.lastname: Castells
authors.forename: Sergi
authors.initials: S
authors.lastname: Castellvi-Bel
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
mesh_terms: D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D019295:Computational Biology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D060005:Genotyping Techniques; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012984:Software
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