It has been recently proposed that GWAS signals that have been credited to common variants could instead reflect the effect of MRVs. Dickson et al. (46) argue that rare variants can create ‘synthetic association' signals in GWAS, by occurring more often in association with one of the alleles of a common tag SNP (Fig. 1), which would thus synthetically confer an increased risk for disease. This might also mean that the causal variants could be megabases away from the common variants detected in GWAS, and that the real effect size could be much stronger than that implied by the common tag SNP. If true, the synthetic association hypothesis would suggest that follow-up studies from GWAS hits should encompass a much larger region than the linkage disequilibrium region surrounding the detected common variant (6).
