Harvesting Medical Information from the Human Family Tree

摘要

Acentral goal of human genetics is to identify and understand causal links between variant forms of genes and disease risk in patients. To date, most progress has been made studying rare, Mendelian diseases in which a mutation in a single gene acts strictly in a deterministic manner, that is, the mutation causes the disease. The fact that such mutations strictly cosegregate with disease in families offers a shortcut to identifying the relevant chromosomal region, and means that the enrichment of mutations in patients with the disease compared with healthy controls can be convincingly documented in small numbers of individuals. In contrast, common diseases typically are caused by a complex combination of multiple genetic risk factors, environmental exposures, and behaviors. Because mutations involved in complex diseases act probabilistically—that is, the clinical outcome depends on many factors in addition to variation in the sequence of a single gene—the effect of any specific mutation is smaller. Thus, such effects can only be revealed by searching for variants that differ in frequency among large numbers of patients and controls drawn from the general population.