Review
The genetics of complex diseases

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Abstract

Genetic factors influence virtually every human disorder, determining disease susceptibility or resistance and interactions with environmental factors. Our recent successes in the genetic mapping and identification of the molecular basis of mendelian traits have been remarkable. Now, attention is rapidly shifting to more-complex, and more-prevalent, genetic disorders and traits that involve multiple genes and environmental effects, such as cardiovascular disease, diabetes, rheumatoid arthritis and schizophrenia. Rather than being due to specific and relatively rare mutations, complex diseases and traits result principally from genetic variation that is relatively common in the general population. Unfortunately, despite extensive efforts by many groups, only a few genetic regions and genes involved in complex diseases have been identified. Completion of the human genome sequence will be a seminal accomplishment, but it will not provide an immediate solution to the genetics of complex traits.

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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