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  • Review Article
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Patterns of linkage disequilibrium in the human genome

Nature Reviews Genetics volume 3, pages 299–309 (2002)Cite this article

A Correction to this article was published on 01 July 2002

Key Points

  • When alleles from different loci are found together in a population, at higher than expected frequencies, they are said to be in linkage disequilibrium (LD). Levels of LD are highest for loci that are physically close in the genome and are reduced by recombination and recurrent mutations.

  • If a disease locus is in LD with linked markers, geneticists can detect the presence of the disease locus by assessing the association between the markers and the disease. This has proved to be a useful strategy for mapping monogenic disease genes, and it is now important to determine whether the same strategy could be applied to complex diseases.

  • One of the issues that needs to be resolved is how best to measure LD. At present, several measures are in use (such as D′, r2 and 4Ner), which means that it is difficult to compare studies.

  • Extensive studies of LD have been conducted in natural populations of Drosophila species, and have shown that LD is variable in different regions of the genome, and is influenced by selective forces, in addition to variation in rates of recombination. Hitchhiking effects can increase LD whilst reducing levels of nucleotide diversity in a region.

  • In humans, simulation studies have provided some useful insights into the factors that are likely to shape patterns of diversity and LD in the human genome. However, it is clear from several studies that simple models of human demography cannot account for the observed levels and variation in nucleotide diversity.

  • These studies emphasize the interplay of many factors in shaping patterns of LD. Factors include genetic drift, selection, demographic factors, variable rates of mutation, recombination and gene conversion.

  • The recent expansion of human genomic resources has provided the impetus for many empirical studies of human LD. Such studies highlight the variation that is seen in different parts of the genome. It is not clear, at present, whether there will also be variation between populations with different demographic histories.

  • The main practical implication of these findings for the study of complex disease is that pilot studies of a genomic region in the population of interest will be essential before a suitable strategy can be devised to look for an association between markers and disease susceptibility.

Abstract

Particular alleles at neighbouring loci tend to be co-inherited. For tightly linked loci, this might lead to associations between alleles in the population — a property known as linkage disequilibrium (LD). LD has recently become the focus of intense study in the hope that it might facilitate the mapping of complex disease loci through whole-genome association studies. This approach depends crucially on the patterns of LD in the human genome. In this review, we draw on empirical studies in humans and Drosophila, as well as simulation studies, to assess the current state of knowledge about patterns of LD, and consider the implications for the use of LD as a mapping tool.

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Figure 1: Linkage disequilibrium around an ancestral mutation.
Figure 2: Optimal mapping strategies for different types of loci.
Figure 3: The erosion of linkage disequilibrium by recombination.

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Acknowledgements

We are grateful to M. Eberle for carrying out the simulations presented in Box 2. The manuscript was greatly improved by suggestions from three anonymous referees. Supported in part by a grant from the National Institutes of Mental Health (to L.K.). L.K. is a James S. McDonnell Centennial Fellow. M.S. is supported by the National Human Genome Research Institute.

Author information

Authors and Affiliations

  1. Genomics Collaborative, 99 Erie Street, Cambridge, 02139, Massachusetts, USA

    Kristin G. Ardlie

  2. Howard Hughes Medical Institute and Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D4-100, Seattle, 98109, Washington, USA

    Leonid Kruglyak

  3. Program for Population Genetics, Harvard School of Public Health, 665 Huntington Avenue, Boston, 02115, Massachusetts, USA

    Mark Seielstad

Authors
  1. Kristin G. Ardlie
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  2. Leonid Kruglyak
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Correspondence to Kristin G. Ardlie, Leonid Kruglyak or Mark Seielstad.

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DATABASES

LocusLink

Pgm

FURTHER INFORMATION

SNP Consortium

Glossary

TEST OF ASSOCIATION

A study that searches for a population association between a phenotype and a particular allele. In one of the simplest such tests — the case–control study — an excess (or deficiency) of a particular allele in a sample of individuals with the phenotype is looked for, as compared with a sample without the phenotype drawn from the same population.

HAPLOTYPE

The combination of alleles found at neighbouring loci on a single chromosome or haploid DNA molecule.

EFFECTIVE POPULATION SIZE

(Ne). An abstraction, equivalent to the breeding population size of an ideal, randomly mating population, which maintains the same level of variation as observed in the actual population. Ne often bears little relation to the actual number of living or reproducing individuals (the census population size), and is generally much smaller.

ADMIXTURE

The introduction of mates (more properly, their genes) from one previously distinct population (the gene frequencies of which might differ) into another.

CLINE

The exhibition of regular and directional variation in phenotype, or genotype, across a geographical region — for example, steadily increasing pigmentation from temperate to tropical latitudes.

PANMIXIS

The process in a population by which mates are chosen at random with equal probability regardless of geographical location or genotype.

NUCLEOTIDE DIVERSITY

A measure of DNA sequence variation that is influenced both by the number of variable sites and their population allele frequencies in a given stretch of DNA.

MINOR ALLELE

The less frequent of two alleles at a locus.

BOTTLENECK

A period when the size of a population is reduced, generally by a large factor.

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Ardlie, K., Kruglyak, L. & Seielstad, M. Patterns of linkage disequilibrium in the human genome. Nat Rev Genet 3, 299–309 (2002). https://doi.org/10.1038/nrg777

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