For schizophrenia, there are multiple reasons for the lack of overlap between GWAS and candidate gene studies. A key possibility is that prior hypotheses about the genetics of schizophrenia are incorrect. However, alternative explanations require exploration before accepting such an important conclusion. First, current GWAS chips provide coverage for most but not all of the genome (International HapMap Consortium, 2005) so particular regions and non-SNP genetic variation may be covered poorly. Second, power may be insufficient. Although GWAS tend to have large sample sizes by historical standards, the necessity to adjust for around a million statistical tests could result in low power. If that is the explanation, support for the hypotheses underpinning previous candidate genes might be obtained by a more systematic analysis of the GWAS data for evidence for over-representation of smaller p-values than expected by chance (Holmans et al., 2009). Third, individually rare genetic variants of strong effect might also be missed by GWAS studies (although these would also go undetected by most prior candidate gene studies).
