Common Disease: Are Causative Alleles Common or Rare?

Article in PLoS Biology:

There have now been over 700 genome-wide association studies (GWAS) published linking many variants to over a hundred diseases. Many of these results are robust in that they can be replicated in several populations, leaving little doubt that common variants can contribute to common diseases. The problem is that the effect of these variants on disease is often rather modest, so that people with the disease-predisposing alleles are only slightly more likely to get the disease than those without. Larger and larger studies reveal more disease genes, usually with smaller and smaller effect on overall disease risk. The “missing heritability” problem then arises because, even in aggregate, these loci typically fall somewhat short of explaining the entire genetic component of disease risk.