title: Elements of 'missing heritability'.
abstract: OBJECTIVE
  To discuss the basis of 'missing heritability', which has emerged as an enigma in the post-genome-wide association studies (GWAS) era.
  
  
  RESULTS
  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'.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center and Texas Heart Institute, Houston, Texas 77030, USA. Ali.J.Marian@uth.tmc.edu
authors.forename: Ali J
authors.initials: AJ
authors.lastname: Marian
mesh_terms: D000483:Alleles; D057890:Epigenomics; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype