Pairwise shared genomic segment analysis in high-risk pedigrees: application to Genetic Analysis Workshop 17 exome-sequencing SNP data.

We applied our method of pairwise shared genomic segment (pSGS) analysis to high-risk pedigrees identified from the Genetic Analysis Workshop 17 (GAW17) mini-exome sequencing data set. The original shared genomic segment method focused on identifying regions shared by all case subjects in a pedigree; thus it can be sensitive to sporadic cases. Our new method examines sharing among all pairs of case subjects in a high-risk pedigree and then uses the mean sharing as the test statistic; in addition, the significance is assessed empirically based on the pedigree structure and linkage disequilibrium pattern of the single-nucleotide polymorphisms. Using all GAW17 replicates, we identified 18 unilineal high-risk pedigrees that contained excess disease (p < 0.01) and at least 15 meioses between case subjects. Eighteen rare causal variants were polymorphic in this set of pedigrees. Based on a significance threshold of 0.001, 72.2% (13/18) of these pedigrees were successfully identified with at least one region that contains a true causal variant. The regions identified included 4 of the possible 18 polymorphic causal variants. On average, 1.1 true positives and 1.7 false positives were identified per pedigree. In conclusion, we have demonstrated the potential of our new pSGS method for localizing rare disease causal variants in common disease using high-risk pedigrees and exome sequence data.