Common vs. rare allele hypotheses for complex diseases

Abstract

There has been growing debate over the nature of the genetic contribution to individual susceptibility to common complex diseases such as diabetes, osteoporosis, and cancer. The 'Common Disease, Common Variant (CDCV)' hypothesis argues that genetic variations with appreciable frequency in the population at large, but relatively low 'penetrance' (or the probability that a carrier of the relevant variants will express the disease), are the major contributors to genetic susceptibility to common diseases. The 'Common Disease, Rare Variant (CDRV)' hypothesis, on the contrary, argues that multiple rare DNA sequence variations, each with relatively high penetrance, are the major contributors to genetic susceptibility to common diseases. Both hypotheses have their place in current research efforts.

Figure 1

Hypothetical DNA sequences obtained from cases and controls for a genomic region of interest. The presence of an actual base (as opposed to a simple dot) indicates the presence of a non-reference or alternative allele. Dots indicate that the sequences are consistent with a reference. The shaded rectangles above the sequences reflect known functional elements at the positions indicated in the sequence below. Note that many of the variations possessed by the cases are rare and fall into the functional genomic regions. Relevant hypothesis tests would investigate the collective frequency difference of these variations between the case and control sequences. The definition and justification for grouping rare variations to be tested in this manner is crucial.