GWAS studies to date have focused on single locus tests which are the simplest to generate and to interpret. There are, however, situations where they might not provide most power. Examples include where there are multiple common variants at a locus5, and, for replication studies or meta-analysis, where there are differences in the association signals between populations6. Either of these can give rise to complex patterns of association that might not be reflected by association to the same SNPs in different samples despite apparently reasonably powered samples7,8. Another consideration is that power to detect association might be enhanced by exploiting information from multiple (quasi) independent signals within genes. Although it is unknown to what extent any of the above concerns occur in practice, arguments such as these have led some to advocate the use of gene-wide statistical approaches5.
