Abstract
BackgroundWe applied a new weighted pairwise shared genomic segment (pSGS) analysis for susceptibility gene localization to high-density genomewide SNP data in three extended high-risk breast cancer pedigrees.ResultsUsing this method, four genomewide suggestive regions were identified on chromosomes 2, 4, 7 and 8, and a borderline suggestive region on chromosome 14. Seven additional regions with at least nominal evidence were observed. Of particular note among these total twelve regions were three regions that were identified in two pedigrees each; chromosomes 4, 7 and 14. Follow-up two-pedigree pSGS analyses further indicated excessive genomic sharing across the pedigrees in all three regions, suggesting that the underlying susceptibility alleles in those regions may be shared in common. In general, the pSGS regions identified were quite large (average 32.2 Mb), however, the range was wide (0.3 – 88.2 Mb). Several of the regions identified overlapped with loci and genes that have been previously implicated in breast cancer risk, including NBS1, BRCA1 and RAD51L1.ConclusionsOur analyses have provided several loci of interest to pursue in these high-risk pedigrees and illustrate the utility of the weighted pSGS method and extended pedigrees for gene mapping in complex diseases. A focused sequencing effort across these loci in the sharing individuals is the natural next step to further map the critical underlying susceptibility variants in these regions.
Highlights
We applied a new weighted pairwise shared genomic segment analysis for susceptibility gene localization to high-density genomewide single nucleotide polymorphism (SNP) data in three extended high-risk breast cancer pedigrees
We recently introduced a new shared genomic segment (SGS) test statistic, the weighted mean pairwise Shared Genomic Segment statistic [9]
For pedigree 3, the empirical genomewide suggestive and significance thresholds for pairwise shared genomic segment (pSGS) were p=5.0×10-3 and p=2.5×10-4, respectively, and the suggestive and significant thresholds for SGS were estimated as p=3.8×10-5 and p
Summary
We applied a new weighted pairwise shared genomic segment (pSGS) analysis for susceptibility gene localization to high-density genomewide SNP data in three extended high-risk breast cancer pedigrees. Our SGS methods use excessive lengths of IBS to find regions of IBD. Large high-risk pedigrees may suffer from intra-familial heterogeneity, such as when more than one genetic locus segregates within the same family. In these situations, even at a true risk locus, a greater proportion of the cases may be non-sharers. We proposed an alternate weighted pairwise SGS (pSGS) method, which combines the sharing evidence across all possible pairs, which in simulated data indicated substantial increased robustness to intra-familial genetic heterogeneity and is likely more useful for mapping common diseases [9]
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