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 group of variants affecting the same gene or a set of genes with related functions, and it is assessed to have a substantial probability of affecting the function of the relevant gene product. The challenges of such studies are the choice of candidate genes, the choice of appropriate case groups, the need for extensive DNA resequencing of many genes in comparatively large numbers of individuals, and the assessment of the functional consequences of variants. Most critical of these is the choice of candidate genes made by two main criteria: (i) genes in which obviously severe disruption of function gives rise to a severe, usually clearly familial, version of the disease being studied and (ii) genes known to be involved in the biology of the disease based on biochemical and physiological studies. For example, for cancer, the most obvious candidates are genes that are mutated somatically or epigenetically changed in their expression in a significant proportion of cancers. Case groups should
