At the outset, we assumed it unlikely that a GWAS study would identify the true pathogenic variant. However, a recent study (5) supports the existence of very large numbers of common alleles of weak effect. Power considerations suggest few of these can be expected to achieve high levels of significance even in samples substantially larger than those we used in our discovery GWAS. However, while power to identify any one specific risk allele is low, power to identify one of many alleles is enhanced if there are very many of these to be detected. One factor dictating this will be the degree to which true risk variants are tagged by array SNPs, weak effects requiring very high LD both for detection and reliable directional replication(25). It follows that those risk alleles that by chance are included on arrays are most likely to be detected and replicated. Thus, in the context of a highly polygenic disorder with weak genetic effects and a underpowered discovery sample, those true associations that are first detected by GWAS studies are, as we have observed here, likely to either correspond to susceptibility alleles, or be in perfect LD with them.
