Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits.

Abstract

Multiple methods have been developed to estimate narrow-sense heritability, h2, using single nucleotide polymorphisms (SNPs) in unrelated individuals. However, a comprehensive evaluation of these methods has not yet been performed, leading to confusion and discrepancy in the literature. We present the most thorough and realistic comparison of these methods to date. We utilized thousands of real whole genome sequences to simulate phenotypes under varying genetic architectures and confounding variables, and used array, imputed, or whole genome sequence SNPs to obtain “SNP-heritability” estimates (ĥ2SNP). We show that ĥ2SNP can be highly sensitive to assumptions about the frequencies, effect sizes, and levels of linkage disequilibrium (LD) of underlying causal variants, but that methods that bin SNPs according to minor allele frequency and LD are less sensitive to these assumptions across a wide range of genetic architectures and possible confounding factors. These findings provide guidance for best practices and proper interpretation of published estimates.