TY - JOUR
T1 - Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13
AU - Spain, Sarah L
AU - Carvajal-Carmona, Luis G
AU - Howarth, Kimberley M
AU - Jones, Angela M
AU - Su, Zhan
AU - Cazier, Jean-Baptiste
AU - Williams, Jennet
AU - Aaltonen, Lauri A
AU - Pharoah, Paul
AU - Kerr, David J
AU - Cheadle, Jeremy
AU - Li, Li
AU - Casey, Graham
AU - Vodicka, Pavel
AU - Sieber, Oliver
AU - Lipton, Lara
AU - Gibbs, Peter
AU - Martin, Nicholas G
AU - Montgomery, Grant W
AU - Young, Joanne
AU - Baird, Paul N
AU - Morreau, Hans
AU - van Wezel, Tom
AU - Ruiz-Ponte, Clara
AU - Fernandez-Rozadilla, Ceres
AU - Carracedo, Angel
AU - Castells, Antoni
AU - Castellvi-Bel, Sergi
AU - Dunlop, Malcolm
AU - Houlston, Richard S
AU - Tomlinson, Ian P M
PY - 2012/2/15
Y1 - 2012/2/15
N2 - 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.
AB - 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.
KW - Chromosome Mapping
KW - Chromosomes, Human, Pair 1
KW - Chromosomes, Human, Pair 12
KW - Colorectal Neoplasms
KW - Computational Biology
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Genotyping Techniques
KW - Haplotypes
KW - Humans
KW - Logistic Models
KW - Polymorphism, Single Nucleotide
KW - Software
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84863040184&partnerID=MN8TOARS
U2 - 10.1093/hmg/ddr523
DO - 10.1093/hmg/ddr523
M3 - Article
C2 - 22076443
SN - 0964-6906
VL - 21
SP - 934
EP - 946
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 4
ER -