Trends in Biochemical Sciences
ReviewThe genetics of complex diseases
Section snippets
Mendelian traits
There are three main approaches to mapping the genetic variants involved in a disease: functional cloning, the candidate gene strategy and positional cloning3. In functional cloning, identification of the underlying protein defect leads to localization of the responsible gene (disease–function–gene–map). An example of functional cloning was the finding that individuals with sickle-cell anaemia carried an amino acid substitution in the β chain of haemoglobin. Isolation of the mutant molecule led
Mapping mendelian and complex traits
An array of approaches is available to uncover the different genetic facets of mendelian and complex traits and diseases7, 8, 9, 10. Two complementary analytical methods, linkage analyses and association (linkage disequilibrium) mapping, are used to detect the specific genetic regions and genes that are involved in the disease process. These approaches can be applied, without prior knowledge of the biological basis of the disease, using genome-wide studies, together with the candidate-gene
Complex diseases
Association studies have been applied most successfully in mapping complex diseases to the human leukocyte antigen (HLA) region on chromosome 6 (Ref. 19). The HLA region contains ∼200 genes, many of which are involved in the immune response. Association (Table 1) and affected sib-pair linkage studies have implicated genes of the HLA region in the aetiology of more than 100 diseases18, 19. The associations are often very strong, for example, over 90% of patients with ankylosing spondylitis carry
The future
Both functional and positional cloning of mendelian traits and diseases are now relatively straightforward, and, with the completion of the HGP, they will become practically routine3. An immediate benefit of the completion of the HGP will be an increase in the use of positional candidate-gene analyses. The ability to identify candidate genes in a region that has already been identified by positional cloning can greatly reduce the time required to target the actual gene involved in the disease.
Acknowledgements
We thank M. Nelson for preparing Fig. 1 and L. Barcellos, M. Grote, J. Hollenbach, L. Louie, K. Mather, S. McWeeney, D. Meyer, E. Mignot, M. Nelson, H. Payami, D.C. Rao, J-X. She and A.M. Valdes for helpful input on the manuscript. The work was supported by NIH grant GM56688.
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