Dickson et al. define synthetic association as the association of a genotyped common marker resulting from multiple unobserved low-frequency causal variants (see Figure 1). The variance contributed by the causal variants would be much higher than variance explained by the associated genotyped SNP, because the genotyped SNPs will not “tag” (see Box 1) the causal variants with great precision, thus leading to the “missing” heritability from GWAS. Importantly, synthetic associations may arise many hundreds of kilobases (kb) from the site of the causal variant(s), which would hamper attempts to locate the causal variants responsible for association signals by fine-mapping. Dickson et al. claim that rare variants can give rise to synthetic associations that are similar to many observed GWAS associations. As we show below, however, synthetic associations in fact tend to differ in some important ways to observations from GWAS. Furthermore, even if rare variants can, in principle, give rise to associations detectable in GWAS, the converse proposition (that, for a given trait, many, or even any, detected GWAS associations arise from rare variants) does not automatically follow.
