missing heritability

Dermitzakis ET & Clark AG 2009 Life after GWA studies. Science 326:239-240.

• genome-wide association findings should be integrated into a wider scope of information, including biological processes and environments

• the heritability of stature is 80%
• yet the top 20 candidate genetic variants identified in GWA analyses explain only 3% of the variance
• possible reasons include missing low-frequency alleles, genetic heterogeneity of the trait, genotype-environment interaction, and epistasis

• a major breakthrough will be to predict and interpret the effect of mutational and biochemical changes in human cells and understand how this signal is transmitted spatially (among tissues) and temporally (spanning development)

• to date, GWA studies have relied on a rather unlikely model for the genetics of complex traits − that common DNA sequence variations (known as single-nucleotide polymorphisms) with widespread (but marginal) effects will predominate
• this was a sensible place to start, but perhaps it should not be surprising that common variants provide little help in predicting risk