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

Heritability, h², is a foundational concept in genetics, critical to understanding the genetic basis of complex traits. Recentlyadeveloped methods that estimate heritability from genotyped SNPs, h²_SNP, explain substantially more genetic variance than genomeawide significant loci, but less than classical estimates from twins and families. However, h²_SNP estimates have yet to be comprehensively compared under a range of genetic architectures, making it difficult to draw conclusions from sometimes conflicting published estimates. Here, we used thousands of real whole genome sequences to simulate realistic phenotypes under a variety of genetic architectures, including those from very rare causal variants. We compared the performance of ten methods across different types of genotypic data (commercial SNP array positions, whole genome sequence variants, and imputed variants) and under differing causal variant frequencies, levels of stratification, and relatedness thresholds. These results provide guidance in interpreting past results and choosing optimal approaches for future studies. We then chose two methods (GREMLaMS and GREMLaLDMS) that best estimated overall h²_SNP and the causal variant frequency spectra to six phenotypes in the UK Biobank using imputed genomeawide variants. Our results suggest that as imputation reference panels become larger and more diverse, estimates of the frequency distribution of causal variants will become increasingly unbiased and the vast majority of trait narrowasense heritability will be accounted for.