of the causal variants because causal alleles will segregate to opposite common alleles. In other words, no common variant will be able to partition the rare variants on a genealogy to create a large enough imbalance to create association. We also investigated trends in association with causal variants and found that even though our model specified that only derived alleles at causal sites are deleterious, more than a third of the most highly associated common SNPs showed a higher penetrance for the ancestral allele. This result follows observed patterns [9]. Another important trend is that if only rare variants are contributing to the disease class in a region, the risk allele frequency of the most significant synthetic association will tend toward the low end of the distribution of more common allele frequencies (median = 0.10), although over 20% of genome-wide significant synthetic associations had a risk allele frequency above 0.25 (Figure 5). Of course, this trend is noted when all common variants in a region are included, which is not the case with the available commercial genotyping chips, which have a greater probability of including more common variants. In this case, the skew towards lower-frequency variants would be less.
