Haplotype Heritability Mapping Method Uncovers Missing Heritability of Complex Traits

We propose a novel approach to analyze genomic data that incorporates haplotype information for detecting rare variants within a regional heritability mapping framework. The performance of our approach was tested in a simulation study based on human genotypes. The phenotypes were simulated by generating regional variance using either SNP(s) or haplotype(s). Regional genomic relationship matrices, constructed with either a SNP-based or a haplotype-based estimator, were employed to estimate the regional variance. The results from the study show that haplotype heritability mapping captures the regional effect, with its relative performance decreasing with increasing analysis window size. The SNP-based regional mapping approach often misses the effect of causal haplotype(s); however, it has a greater power to detect simulated SNP-based-variants. Heritability estimates suggest that the haplotype heritability mapping estimates the simulated regional heritability accurately for all phenotypes and analysis windows. However, the SNP-based analysis overestimates the regional heritability and performs less well than our haplotype-based approach for the simulated rare haplotype-based-variant. We conclude that haplotype heritability mapping is a useful tool to capture the effect of rare variants, and explain a proportion of the missing heritability.