The study of Dickson et al. [4] is the first to consider, in detail, a genetic architecture of multiple rare variants within the framework of GWAS analyses. For ease of discussion, we use the terms rare, common, and very common alleles, but the cut-offs between them is necessarily somewhat arbitrary. For the purposes of simulation, Dickson et al. define rare variants as having risk allele frequency (RAF) 0.005–0.02 and define common SNPs to be representative of those used in GWAS studies (minor allele frequency, MAF>0.05). An important proportion of GWAS associations have risk alleles in the very common frequency spectrum (RAF>0.3) (Figure 2a). We will show that it is unlikely that such associations are driven by synthetic associations with single or multiple rare causal variants. We set out to understand and clarify their model and its implications in order to answer three questions:
