Variant Prioritization by Pedigree-Based Haplotyping.

Whole genome sequence (WGS) data provides opportunities for comprehensive evaluation of variants that may influence complex traits. However, prioritizing the large number of variants, particularly those in non-coding regions, is a challenge. Here we present an approach that uses pedigree-based haplotyping to identify the risk haplotype and resulting set of prioritized variants in a region of interest (ROI) defined by identity-by-descent (IBD) sharing among familial cases. The approach is applicable for use in both a full range of pedigree sizes and for the full allele frequency spectrum of variants without the need for a large reference sample. By determining haplotype sharing among individuals with WGS data, we demonstrate the ability to accurately identify a risk haplotype and a strongly reduced list of potential risk alleles for a trait of interest along with the cases who carry the risk haplotype. This is important in the context of complex traits where the disease may be etiologically heterogeneous even within a single pedigree. Application to both simulated and real Alzheimer's disease family data shows that the approach leads to accurate risk-haplotype identification with marked reduction in the number of potential trait-associated variants. Simulation also shows that the approach provides accurate risk haplotypes in ROIs.