While the above-mentioned plausible contributors seem unlikely to play a substantial role in explaining missing heritability, rare variants are increasingly thought to account for a large proportion of it (34–36). Contrary to the CDCV hypothesis, the multiple rare variant (MRV) hypothesis argues that the summation of the effects of low-frequency polymorphisms, each conferring an intermediate increase in risk (i.e. incompletely penetrant, but greater than those observed for common variants), can explain a significant proportion of the genetic susceptibility to common diseases and traits. Some studies analysing rare variants using GWAS data have been carried out, but these have proven to be underpowered to detect robust associations. Re-sequencing approaches are more suitable for rare variant analysis, and, as these are becoming more cost-effective and new analysis methods are being developed (37,38), they will soon be applied to large-scale studies of rare variants. Indeed, several targeted sequencing studies have already proven successful for the identification of associations between rare variants and some human diseases and disease-related phenotypes (39–43). The same argument can also be extended to other forms of genetic variation, and
