The exact contributions of rare and common genetic variants to the underpinnings of AD remain unknown, but consistent with both the neutral and selection theories of genetic variation, our results, principally those for the EA sample, point to a strong likelihood for a concentration of weak causal variants from the low end of the MAF spectrum that can lurk beneath stringent genome-wide significance boundaries (Heath et al. 2011). Moreover, these findings support the theoretical possibility of “synthetic association”, a phenomenon described and coined by Dickson et al. (2010), in which the aggregate risk effects of extended genomic blocks of rare variants can create genome-wide significant associations with weakly tagged, common SNP markers, complicating the interpretation of GWAS results as it relates to the localization of causal variants. Despite other simulation studies and empirical evidence that lend support to this genetic mechanism of association, including the well-known instance involving the NOD2 locus and Crohn’s disease (Anderson et al. 2011), several recent papers have disputed the prevalence of synthetic association for complex phenotypes, drawing upon the paucity of replicable linkage signals that
