Explaining this ‘missing heritability' of complex diseases (11–13) is an area of active research, and there are likely to be multiple contributing factors. Part of the explanation is likely to be an underestimate of the contribution made by the types of variants targeted by GWAS. For instance, it might be that there are large numbers of variants of very small effect, which early GWAS were underpowered to detect, yet to be found. This idea is supported by the observation that meta-analyses of published GWAS are discovering a substantial number of new susceptibility loci (14–25). In addition, for most loci, causal variants and potential independent additional markers within the region have not been identified yet. New ways of analysing the genetic architecture of complex traits using GWAS data are suggesting that indeed a large proportion of heritability can be explained by common variants and that larger GWAS will yield many more validated loci for complex traits (26,27).
