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 should be amenable to similar rare variant effects (Orozco et al. 2010; Anderson et al. 2011), as well as the modality of GWAS marker signals towards higher frequencies (Wray et al. 2011) and the observance of trans-ethnic associations (Waters et al. 2010). Although our findings indicate the plausibility of recapitulating rare variant effects through polymarker scores derived from common GWAS markers (e.g., 0.3 ≤ MAF < 0.4), this should not be interpreted as support of a rare variant-only model for the genetic architecture of alcoholism, as mixed models also exhibit robust fits (Fig. S5). The simulations conducted here represent only a cursory exploration of potential disease models, and thus does not discount other neutral evolutionary models for common genetic variation, especially given the positive relationship between risk allele frequency and disease variance explained (Visscher et al. 2012).
