collection of hundreds, or possibly even thousands, of similar conditions attributable to rare variants at individual loci18. If each of these variants explains most of the risk in just a handful of people, their effects will not explain enough of the variance in a total population to be detected by standard GWAS procedures. The total number of loci that may contribute to any disease is a function of the baseline disease incidence, the number of rare variants per locus, and the genotypic relative risk (GRR, namely, effect size). For a disease with a high heritability of 80%, theory indicates that the number of contributing loci can range from over 500 with GRR of just 2 and one very rare variant per locus, to just a dozen loci with GRR of 5 and allele frequencies of 1% or if the disease is relatively common19.
