Interestingly, both our linkage and association analyses, from the primary and replication analyses, suggest that low frequency (<0.05) minor alleles may be common in autism. Intriguingly, the linkage studies reveal low frequency susceptibility alleles whereas the association analyses have uncovered rare alleles with odds ratios less than 0.6 (the common alleles in the population associated with increased risk for autism). This can occur when the ancestral allele, that was previously neutral or beneficial, now has detrimental effects revealed by an evolutionarily recent environment, or when a pleiotropic function of the allele is selectively advantageous, or when this variation is hitchhiking on a shared haplotype with a distinct beneficial allele 22. However, it is worth noting that our study design of ascertaining multiplex families is not well-powered to identify loci under this genetic model of common major alleles associated with autism susceptibility.
