The nearly 400 GWAS published so far represent a wealth of data on the genetics of complex diseases4. These studies have provided valuable insights into the genetics of common diseases, particularly about the underlying genetic architecture of complex traits and the predominance of non-coding variants that may have a role in their aetiology. Just as linkage studies demonstrated that complex diseases cannot be explained by a small number of rare variants with large effects, GWAS have shown that they cannot be explained by a limited number of common variants of moderate effect (Fig. 1). The distinction between low frequency and truly rare alleles is largely an operational one, relating to the potential, given realistic effect sizes, for detecting associations with low frequency variants by GWAS at attainable sample sizes. Low frequency variants of intermediate effect might also contribute to explaining missing heritability that should be tractable through large meta-analyses and/or imputation of genome-wide association data.
