Common diseasecommon variant or not

One hypothesis that has become popular in recent years is that much of the genetic variation underlying complex traits is made up of common alleles (Lander, 1996; Chakravarti, 1999). This idea, often referred to as the ''common disease-common variant'' (CD-CV) hypothesis, has important implications for disease mapping, because it suggests that genome-wide association mapping should be an extremely powerful tool for identifying the variants that contribute to complex traits. An alternative model is that at most complex disease loci there are a few, or even many different alleles that all impact risk. This is the situation that is observed for most rare Mendelian traits. When the latter scenario occurs, the strength of association at single SNPs, or with haplotypes will usually be substantially weakened (Slager et al., 2000), and so association mapping will be more difficult.

At the time of writing, there are not enough data to be able to evaluate the extent to which the CD-CV hypothesis is true. There are a number of examples of common variants for complex diseases that are known (Lohmueller et al., 2003), and also clear examples of moderate allelic heterogeneity (at NOD2/CARD15, involved in Crohn's disease; Hugot et al., 2001) and functional rare variants (associated with plasma levels of HDL cholesterol and LDL, and rates of sterol absorption; Cohen et al., 2004; 2006). However, there is a clear ascertainment bias here. Relatively few complex trait loci have been identified thus far, and it is to be expected that many of the first loci to be discovered will be genetically simpler than the average.

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