We showed that rare coding variants available on the exome chip or imputable by the Haplotype Reference Consortium, with frequency <1%, explain significant proportions of phenotypic variance, and a substantial proportion of the total SNP heritability. The exome chip was designed to genotype coding variants uncovered in ~12,000 sequenced exomes. By design, it comprehensively ascertained high confidence rare nonsynonymous, splice, and stop variants within those sequences and only sparsely genotypes other classes of variation, including common variants. The Haplotype Reference Consortium panel imputed data also have limited accuracy when the underlying genetic variants are rare. Therefore, our current investigation did not fully explore the genetic architecture of very rare variants (i.e. with MAF<0.1%). With the development of larger imputation reference panels, and the availability of large scale deep whole genome sequences (such as the Trans-Omics for Precision Medicine Study [TOPMed]), we expect to be able to conduct an even more comprehensive analysis of the genetic architecture for variants with ever lower frequencies. Ultimately, the discovery of low frequency with small effects will require even larger sample sizes. For example, for
