Genetic Architecture of Complex Human Traits: What Have We Learned from Genome-Wide Association Studies?

Genome-wide association studies have identified thousands of genetic variants associated with various complex human traits and diseases. These results opened a window to the genetic architecture of complex human traits. The fact that the identified variants usually confer small effects and explain only a small fraction of heritability has led the discussion of where to find the ‘missing heritability.’ Two competitive models have been proposed: the ‘infinitesimal model’ suggests large number of variants of small effects and the ‘rare variant model’ suggests multiple large-effect rare variants. Recent empirical studies and theoretical analyses suggest that the infinitesimal model might dominate the true genetic architecture of most complex traits. Large-effect rare variants may exist and might be functionally important but contribute little to heritability.