Power calculations comparing a large-scale linkage scan (52) with the largest GWAS considered by Dickson et al. (46) show that only a small fraction of the genetic models which can give rise to synthetic associations would not be detected by linkage. Furthermore, the scenario where synthetic associations could have escaped linkage comprises models with a small number of causal variants with genotype relative risk <2.5 (53). While these observations do not entirely rule out synthetic associations, they seriously confine the parameter space in which they might exist. In addition, comparisons of even modest linkage signals with GWAS regions have shown only a few overlaps, and even these are largely driven by atypically large effects like the MHC in autoimmunity. In addition, attempts to explicitly use linkage information to boost the power of GWAS (54) have not been successful. This contrast between largely overlapping genetic models that linkage and synthetic association are well powered to detect and almost completely non-overlapping results from linkage and GWAS strongly suggests that synthetic associations do not underlie many GWAS signals.
