Lupu, T. V.; Wright, H. I. W.; Armirola-Ricaurte, C.; Huerta-Chagoya, A.; Wood, A. R.; Mercader, J. M.; Manning, A. K.; Hysong, M.; Barroso, I.; Wright, C. F.; Weedon, M. N.; Beaumont, R. N.; Chundru, V. K.; Hawkes, G.

Most heritability studies have focused on common genetic variation and have largely excluded non-European or highly admixed populations. Here, we estimated the whole-genome heritability (h2WGS) of seven complex traits using 73,600,953 autosomal and chromosome X variants for 198,931 unrelated individuals from three genetic similarity groups. Adjusting for population stratification, we showed that rare variants (minor allele frequency<0.01) explain 30.6-67.7% of h2WGS. We used simulations to show how functionally-stratified heritability can be inflated due to linkage with missing or lower-quality variants. Finally, after accounting for confounding effects, we found substantial heritability enrichment from variants in non-coding RNA exons (maximum fold enrichment, FE=8.7, P=3.56e-7), UTRs (23.0, P=3.46e-30), distal regulatory regions (33.8, P=3.26e-42), and protein-coding exons (58.0, P=7.78e-15). Our study provides a framework for investigating the genetic architecture of complex human phenotypes using diverse whole-genome sequencing data and highlights the contribution of rare and non-coding genetic variants to the heritability of complex traits.