Common variants, rare variants or rare combinations of common variants?

Terwilliger and Göring claimed in their 2000 paper "that a larger number of less common alleles is likely to be involved in the etiology of complex disease". They now claim that the grand failure of GWAS and the common variant/common disease(CVCD) hypothesis of Reich and Lander (2001) validates this claim. Their new paper in Human Biology is an interesting read and it is certainly fun to see them slam GWAS. However, I am not yet convinced that the 'missing heritability' is largely due to rare variants. I think it is still highly likely that common variants are important through gene-gene and gene-environment interactions. It is important to note that genotype combinations from multiple common variants are inherently rare in the population. The rare variant effects that everyone is now so excited about might very well be right under our noses. I pointed this out in a recent Nature Reviews Genetics viewpoint piece (see May 18, 2010 post below).

Terwilliger JD, Göring HH. Update to Terwilliger and Göring's "Gene mapping in the 20th and 21st centuries" (2000): gene mapping when rare variants are common and common variants are rare. Hum Biol. 2009 Dec;81(5-6):729-33.

Terwilliger JD, Göring HH. Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design. Hum Biol. 2000 Feb;72(1):63-132.

Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH. Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet. 2010 Jun;11(6):446-50.

Reich DE, Lander ES. On the allelic spectrum of human disease. Trends Genet. 2001 Sep;17(9):502-10.

Note added June 15: Here is a recent blog post I ran across on the same paper: Getting Genetics Done