The design of current GWAS makes them suitable mainly for the discovery of common variants conferring low/moderate risks, in the context of the common disease/common variant hypothesis (CDCV).11 Given the current near impossibility of reliably detecting effects of rare alleles (owing to sample size and sequencing constraints), most of GWAS have analyzed single nucleotide polymorphisms (SNPs) with minor allele frequencies of more than 5%. Rare variants, with frequencies lying somewhere between the limits of deleterious mutations and polymorphic variations (i.e. 0.1–1%) are not examined by current GWAS. According to an alternative hypothesis (common disease/rare variant hypothesis), complex traits are caused collectively by multiple rare variants with moderate to high penetrance.12 Evolutionary theories, empirical evidence and data from the HapMap project support this hypothesis.13 Because of their low frequency and individually small contributions to the overall inherited disease susceptibility, rare variants will not be detectable by population association studies based on the use of linked polymorphic markers. Consequently, if the CDCV hypothesis does not hold, or at least holds only in some of the cases, then the “missing heritability” will not
