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Prospects for whole-genome linkage disequilibrium mapping of common disease genes

Nature Genetics volume 22, pages 139–144 (1999)Cite this article

Abstract

Recently, attention has focused on the use of whole-genome linkage disequilibrium (LD) studies to map common disease genes. Such studies would employ a dense map of single nucleotide polymorphisms (SNPs) to detect association between a marker and disease. Construction of SNP maps is currently underway. An essential issue yet to be settled is the required marker density of such maps. Here, I use population simulations to estimate the extent of LD surrounding common gene variants in the general human population as well as in isolated populations. Two main conclusions emerge from these investigations. First, a useful level of LD is unlikely to extend beyond an average distance of roughly 3 kb in the general population, which implies that approximately 500,000 SNPs will be required for whole-genome studies. Second, the extent of LD is similar in isolated populations unless the founding bottleneck is very narrow or the frequency of the variant is low (<5%).

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Figure 1: LD around a variant of 50% frequency in the general human population.
Figure 2: LD around a variant of 10% frequency.
Figure 3: Distributions of variant age.
Figure 4: LD around a variant of 50% frequency for different expansion times.
Figure 5: LD around a variant of 50% frequency for different ancestral population sizes.
Figure 6: LD in an isolated population.
Figure 7: LD under different scenarios of population growth.

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Acknowledgements

This work grew out of conversations with E. Lander, and I am grateful for his advice and encouragement. I thank D. Altshuler, K. Ardlie, M. Cargill, H. Coller, G. Daley, M. Daly, M. Eberle, J. Felsenstein, S. Kruglyak, S.-N. Liu, K. Markianos, D. Slonim, D. Wang and E. Wijsman for helpful discussions and comments on the manuscript, and M. Eberle for invaluable assistance with simulations and figure preparation. The paper benefited from discussion during a meeting on SNPs held at the Banbury Center and from comments of anonymous referees. This work was supported in part by grants from NHGRI and NIMH. L.K. is a James S. McDonnell Centennial Fellow.

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  1. Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, 98109, Washington, USA

    L Kruglyak

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Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22, 139–144 (1999). https://doi.org/10.1038/9642

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