One general observation emerging from genome-wide association studies (GWAS) of complex human diseases is that common genetic variants can typically account for only a small fraction of the overall disease heritability (1,2). This observation is often referred to as the ‘missing heritability’ property of GWAS (1,3–8). Several possible sources for missing heritability have been discussed in the literature (1,4,7,8), including contributions from untyped rare variants, epistatic interactions between loci and gene-by-environment interactions. It is also widely acknowledged that many common variants associated with complex diseases remain undiscovered (5,9,10). As a result, the potential contribution of rare variation and different types of interactions notwithstanding, a certain proportion of the missing heritability is likely to be explained by the additive contribution of a large number of small-effect common variants, which are yet to be identified.
