Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P ¼ 0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD ¼ 2.79; P ¼ 0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P ¼ 0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL ¼ 0. 1 It is therefore likely that a significant proportion of inherited predisposition to CRC is mediated through susceptibility to CRAs. These observations have provided a strong rationale for searching of novel predisposition genes through genome-wide linkage screens (GWLSs) of hereditary non-FAP/HNPCC CRC families (hereditary nonsyndromic colorectal cancer -HNSCRC). Using a high-density SNP array, we have previously performed a GWLS of 69 HNSCRC families in which involvement of known predisposition genes had been excluded and a novel CRC susceptibility locus at 3q21 -q24 was identified. 5 Other workers have proposed additional loci for CRC susceptibility genes on the basis of linkage, most notably on 9q22.2 -31.2. 6,7 To further examine the impact of unknown moderate/ high-penetrance genes on CRC risk, we conducted a further GWLS on an additional 34 HNSCRC families using the same analytical platform employed in our first analysis. We then pooled data from scans. In an effort to predict the most likely location of the putative CRC gene on 3q21 -q24, we undertook linkage disequilibrium (LD) mapping at 1676 tagging SNPs in 620 HNSCRC cases and 961 controls. In addition, we have sought to identify disease-causing variants by direct mutational analysis of candidate genes localizing to the region of maximal linkage on 3q22. Materials and methods Ascertainment and collection of families and casesFor clarity, we refer to our previously reported GWLS of 69 pedigrees as phase 1 8 and the current analysis of 34 pedigrees as phase 2. As before, familial CRC cases were ascertained through the COloRectal tumour Gene Identification (C...
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