Clearly, part of this missing variance is related to coverage of the existing GWAS chips. By design, GWAS test for association with common variants (allele frequencies > 5%). The less common (or “rare” variants with allele frequencies < 5%) are not adequately represented on the existing arrays. For example, the well known genetic variants that alter alcohol metabolism, rs1229984 in ADH1b and rs671 in ALDH2, are not queried on most of the commercial GWAS chips. Although individually rare, these variants are collectively frequent, and their contribution to disease can be greater than those observed for common variants (Bodmer and Bonilla, 2008). Several other rare mechanisms can contribute to the modest explanation of variance to date. Structural variants, which include insertions and deletions, inversions, and translocations, can account for some of the unexplained heritability. Sequencing will be needed to allow us to definitively detect and test this class of variation.
