title: Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes.
abstract: We have previously identified several colorectal cancer (CRC)-associated polymorphisms using genome-wide association (GWA) analysis. We sought to fine-map the location of the functional variants for three of these regions at 8q23.3 (EIF3H), 16q22.1 (CDH1/CDH3) and 19q13.11 (RHPN2). We genotyped two case-control sets at high density in the selected regions and used existing data from four other case-control sets, comprising a total of 9328 CRC cases and 10 480 controls. To improve marker density, we imputed genotypes from the 1000 Genomes Project and Hapmap3 data sets. All three regions contained smaller areas in which a cluster of single nucleotide polymorphisms (SNPs) showed clearly stronger association signals than surrounding SNPs, allowing us to assign those areas as the most likely location of the disease-associated functional variant. Further fine-mapping within those areas was generally unhelpful in identifying the functional variation based on strengths of association. However, functional annotation suggested a relatively small number of functional SNPs, including some with potential regulatory function at 8q23.3 and 16q22.1 and a non-synonymous SNP in RPHN2. Interestingly, the expression quantitative trait locus browser showed a number of highly associated SNP alleles correlated with mRNA expression levels not of EIF3H and CDH1 or CDH3, but of UTP23 and ZFP90, respectively. In contrast, none of the top SNPs within these regions was associated with transcript levels at EIF3H, CDH1 or CDH3. Our post-GWA study highlights benefits of fine-mapping of common disease variants in combination with publicly available data sets. In addition, caution should be exercised when assigning functionality to candidate genes in regions discovered through GWA analysis.
authors.affiliation: Wellcome Trust Centre for Human Genetics and Department of Clinical Pharmacology, University of Oxford, Oxford, UK. luis@well.ox.ac.uk
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jones
authors.forename: Kimberley
authors.initials: K
authors.lastname: Howarth
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Alan
authors.initials: A
authors.lastname: Pittman
authors.forename: Sara
authors.initials: S
authors.lastname: Dobbins
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: Susan
authors.initials: S
authors.lastname: Farrington
authors.forename: James
authors.initials: J
authors.lastname: Prendergast
authors.forename: Evi
authors.initials: E
authors.lastname: Theodoratou
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barnetson
authors.forename: David
authors.initials: D
authors.lastname: Conti
authors.forename: Polly
authors.initials: P
authors.lastname: Newcomb
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: David J
authors.initials: DJ
authors.lastname: Duggan
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics* / Q000378:metabolism; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics* / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D052138:Genes, Neoplasm; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide