A critical feature shared by common and rare variants is that they do not give rise to a familial concentration of cases. This is because the penetrance of such variants, namely, the probability of a given genotype having the disease in question, is low. Assuming, for example, that the penetrance of the heterozygote for a disease susceptibility allele Dd is 10%, it can be shown that for matings Dd × dd, only 1.4% of families even with four offspring will include more than one affected offspring. For a penetrance of 20%, which, as discussed in Box 1 is high even for a variant with an OR of 3, this proportion is still only 5.2%. Only when penetrances are well above 50% does one approach a familial concentration that begins to look like a standard mendelian segregation. Family studies, therefore, are simply not relevant for the discovery and interpretation of either common or rare variants.
