Commentary: Rare alleles, modest genetic effects and the need for collaboration

The article by Khoury et al.1 presents a useful overview of some of the complex issues facing those trying to identify genetic variants underlying common complex disease. They focus on the common disease—common variant model where effect sizes associated with individual genetic variants are small. Undoubtedly this will be the case for most, but not all, variants. An L-shaped or exponential distribution of mutation effect sizes has wide support 2–4 with many variants with small effects, a smaller number with intermediate effects and relatively few with large effects. It could be argued that the genetic variants related to human disease that have been identified to date primarily reflect the study designs used to identify them. Linkage studies conducted among families with multiple cases of disease were successful in identifying highly penetrant variants with large effects. Association studie