RT Journal Article SR Electronic T1 Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits JF bioRxiv FD Cold Spring Harbor Laboratory SP 115527 DO 10.1101/115527 A1 Luke M. Evans A1 Rasool Tahmasbi A1 Scott I. Vrieze A1 Gonçalo R. Abecasis A1 Sayantan Das A1 Doug W. Bjelland A1 Teresa R. deCandia A1 Haplotype Reference Consortium A1 Michael E. Goddard A1 Benjamin M. Neale A1 Jian Yang A1 Peter M. Visscher A1 Matthew C. Keller YR 2017 UL http://biorxiv.org/content/early/2017/03/09/115527.abstract AB Heritability, h2, is a foundational concept in genetics, critical to understanding the genetic basis of complex traits. Recently-developed methods that estimate heritability from genotyped SNPs, h2 SNP, explain substantially more genetic variance than genome-wide significant loci, but less than classical estimates from twins and families. However, h2SNP 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 (GREML-MS and GREML-LDMS) that best estimated overall h2SNP and the causal variant frequency spectra to six phenotypes in the UK Biobank using imputed genome-wide 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 narrow-sense heritability will be accounted for.