Family studies do not have a significant role in the discovery or analysis of either common or rare disease associated variants, both of which have relatively low penetrances at the individual level (Box 1 and Table 2). That is the basis for the need for quite different strategies for the discovery of either type of variant. Common variants depend on large-scale genotyping of large numbers of cases and controls to be sure of the statistical significance of a suspected SNP association. Rare variants depend on extensive resequencing of carefully selected candidate genes in relatively large numbers of carefully chosen cases, together with a thorough analysis of the functional effects of any suspected variants. Both types of studies assume that background genetic and environmental effects are averaged out, so that, in experimental design terminology, it is the ‘marginal’ effect of a variant that is being assessed.
