Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13

Sarah L. Spain, Luis Carvajal-Carmona, Kimberley M. Howarth, Angela M. Jones, Zhan Su, Jean Baptiste Cazier, Jennet Williams, Lauri A. Aaltonen, Paul Pharoah, David J. Kerr, Jeremy Cheadle, Li Li, Graham Casey, Pavel Vodicka, Oliver Sieber, Lara Lipton, Peter Gibbs, Nicholas G. Martin, Grant W. Montgomery, Joanne YoungPaul N. Baird, Hans Morreau, Tom Van wezel, Clara Ruiz-ponte, Ceres Fernandez-rozadilla, Angel Carracedo, Antoni Castells, Sergi Castellvi-bel, Malcolm Dunlop, Richard S. Houlston, Ian P M Tomlinson

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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.

Original languageEnglish (US)
Article numberddr523
Pages (from-to)934-946
Number of pages13
JournalHuman Molecular Genetics
Issue number4
StatePublished - Feb 2012
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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