The synthetic association paradigm is supported [7] by the well-known association between Crohn's disease and NOD2 [8], where three rare coding variants (G881R – MAF:0.04, R675W – MAF:0.01, and L980fs – MAF:0.02) confer high risk for Crohn's (ORs for a carrier and homozygote are 3 and 38, respectively) [9]. None of these variants are present on current GWAS arrays, nor are they individually well-tagged. Nevertheless, extremely strong association is seen at nearby common variants because the aggregate effect size of the low-frequency causal mutations is sufficiently large that it creates genome-wide significant association even at very weak, common, tag SNPs (Figure 1). For example, in the Wellcome Trust Case-Control Consortium (WTCCC) Crohn's genome-wide association study, the most strongly associated SNP in the region is rs4471699 (P = 1.6×10−22, risk allele frequency: 0.52, odds ratio: 1.52) [10]. Furthermore, in a subset of the WTCCC data where cases [11] and controls [8],[12] have been genotyped for the three low-frequency coding mutations, testing for association while conditioning on carrier status of one of these mutations completely ablates the signal at the common SNPs
