Over the last 15 yr, genes responsible for hundreds of inherited human diseases have been identified, enabling clinical diagnosis and the potential for therapeutic intervention. Until very recently, however, success has been limited to so-called monogenic disorders, diseases in which mutation of a single gene is both necessary and sufficient to cause disease in any given individual. Because such mutations are strictly co-inherited with disease, it is possible to use linkage analysis to identify their chromosomal location by analyzing which of a genome-wide set of markers segregates with disease in families. Genes contained within such linked regions become positional “candidates” and are next examined for mutations in affected individuals. For any such candidate gene, proof of causality typically depends on two additional lines of evidence. First, the putative causal changes should be found only in affected individuals. Second, one hopes for a “smoking gun”—that the disease-associated mutations are obviously deleterious to protein function (due to truncation or deletion of a coding region or alteration of a highly conserved residue). Success is typically declared when these criteria are all satisfied: the putative disease gene 1) is located in a chromosomal region that co-segregates with disease in affected families, 2) contains multiple independent mutations that are perfectly associated with disease status in the families, and 3) whose characteristics obviously alter protein function.

Most common diseases are strongly influenced by inheritance, but, to date, relatively few genes have been identified that are responsible for familial clustering of these diseases. Success has been elusive because common diseases are almost all complex disorders, where multiple genes and environmental factors collaborate to cause disease. Because no single gene segregates tightly with disease, it has proven very difficult to confidently localize putative disease genes to chromosomal locations. For this reason, optimistic gene hunters have leapt directly to the latter stage of examining candidate genes for mutations that show association to disease. Typically, however, these candidate genes are based on a biological hypothesis, rather than chromosomal position relative to a linkage study.