For most complex traits, DNA sequence variants that meet the genome-wide significance threshold do not explain the majority of the heritability as estimated by twin and family studies [1]. Heritability (broad sense) is defined as the proportion of phenotypic variance accounted for by genotypic variance within a population. Narrow sense heritability is a special case of broad sense heritability and refers to the proportion of phenotypic variance that is due only to additive genetic effects. The limited heritability explained by significant GWAS findings has led to the so-called “missing heritability” dilemma and subsequent hypotheses have been generated for how to capture the heritable factors contributing to human trait variation [2], [3]. However, others have argued that the proportion of heritability explained by “top GWAS hits” is limited by currently available sample sizes and analytic approaches, and that sub-threshold GWAS signals may capture a much larger proportion of heritability [1], [4]. Indeed, under current experimental conditions, genome-wide significant GWAS findings alone are likely to account for a very small proportion of total risk variants for many complex disorders and by extension a small proportion of heritability.
