Elements of ‘missing heritability’

PURPOSE OF REVIEW: To discuss the basis of 'missing heritability', which has emerged as an enigma in the post-genome-wide association studies (GWAS) era. RECENT FINDINGS: Alleles identified through GWAS account for a relatively small fraction of heritability of the complex phenotypes. Accordingly, a significant part of heritability of the complex traits remains unaccounted for ('missing heritability'). Recent findings offer several explanations, including overestimation of heritability of the complex traits and underestimation of the effects of alleles identified through GWAS. In addition, yet-to-be identified common as well as rare alleles might in part explain the 'missing heritability'. Moreover, gene-gene (epistasis) and gene-environmental interactions might explain another fraction of heritability of complex traits. Moreover, transgenerational epigenetic changes, regulated in part by microRNAs, might also contribute to the 'missing heritability'. SUMMARY: The new findings suggest a multifarious nature of the 'missing heritability'. The findings de-emphasize the focus on delineating the basis of 'missing heritability' and shift the focus to elucidation of the molecular mechanisms by which genomic and genetic factors govern the pathogenesis of the complex phenotypes.