This hypothesis states simply that common disorders are likely influenced by genetic variation that is also common in the population. There are several key ramifications of this for the study of complex disease. First, if common genetic variants influence disease, the effect size (or penetrance) for any one variant must be small relative to that found for rare disorders. For example, if a SNP with 40% frequency in the population causes a highly deleterious amino acid substitution that directly leads to a disease phenotype, nearly 40% of the population would have that phenotype. Thus, the allele frequency and the population prevalence are completely correlated. If, however, that same SNP caused a small change in gene expression that alters risk for a disease by some small amount, the prevalence of the disease and the influential allele would be only slightly correlated. As such, common variants almost by definition cannot have high penetrance.
