Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease

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Abstract

The past two decades have witnessed an explosion in the identification, largely by positional cloning, of genes associated with mendelian diseases. The roughly 1,200 genes that have been characterized have clarified our understanding of the molecular basis of human genetic disease. The principles derived from these successes should be applied now to strategies aimed at finding the considerably more elusive genes that underlie complex disease phenotypes. The distribution of types of mutation in mendelian disease genes argues for serious consideration of the early application of a genomic-scale sequence-based approach to association studies and against complete reliance on a positional cloning approach based on a map of anonymous single nucleotide polymorphism haplotypes.

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Figure 1: Clinical severity increases with severity of amino acid substitution.
Figure 2: Evidence that clinical significance correlates with the degree of cross-species evolutionary conservation.
Figure 3: The genotype risk ratio that is detectable in an association study.

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Acknowledgements

We thank K. Small for technical assistance, and R. Myers and A. Sidow for discussion. This work was supported in part by grants from the National Institutes of Health.

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Correspondence to David Botstein.

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Botstein, D., Risch, N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 33, 228–237 (2003) doi:10.1038/ng1090

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