On the Genetic Origins of Phenotypes in Genome-Wide Association Studies: The SNP Allocation For Estimating Heritability (SAFE-h2) Tool to Explore Additive-only Allelic Effects or Additive and Non-Additive Allelic Effects

Abstract

Polygenicity requires the inclusion of all SNPs to ensure accurate estimation of SNP heritability. However, SNPs with large association p-values should be excluded, as they impose biologically meaningless negative contributions, i.e., downward bias, to heritability estimates. This is demonstrated with simulated data and validated using real-world datasets. We introduce SAFE-h2 as a solution to this dilemma. SAFE-h2 performs heritability profiling and establishes a p-value threshold to filter out SNPs with negative contributions. By examining 74 phenotypes across eight species, SAFE-h2 revealed an average negative contribution of 30 units, imposed by SNPs from the upper-bounds of p-value thresholds. SAFE-h2 also provides a safe p-value interval to minimize false-positive SNP hits and facilitates capturing intra-locus (Ref -alleleSNPi x Ref -alleleSNPi, Ref - alleleSNPi x Alt -alleleSNPi, and Alt -alleleSNPi x Alt -alleleSNPi) additive and non-additive effects within the framework of linear models. The allelic adjustment algorithm of SAFE-h2 revealed considerable uncaptured phenotypic variance when relying on additive effects and improved the SNP heritability estimations by up to 56 units across 50 phenotypes in six species through the combined capture of both additive and non-additive allelic effects.