Because of their low frequency and individually small contributions to the overall inherited susceptibility of a disease, rare variants will not be detectable by population association studies based on the use of linked polymorphic markers, even very large WGAS. Their discovery depends on the strategy used in the search for variants influencing colorectal adenomas22,23 and HDL cholesterol levels24. Candidate genes are first sequenced in each member of the chosen disease group. Variants considered to be rare—that is, those not obviously polymorphic but not as rare as obviously deleterious mutations—are then assessed for their frequency in an appropriate control population. Variants are also assessed for their potential consequences to the function of the relevant gene product by criteria such as occurrence in conserved regions, charge changes, and bulky changes likely to affect protein structure and thus function, and also by direct biochemical or functional assays. A variant is considered a good candidate for an effect on inherited susceptibility if it shows a significant difference in frequency between disease and control groups either singly or, more often, as a member of a
