Linkage Disequilibrium


When two or more polymorphic loci are studied in a population, the interaction between the loci is often expressed in terms of linkage disequilibrium (LD). The loci are in LD if their respective alleles do not associate independently (randomly). LD does not necessarily imply physical linkage, however most often the loci considered are on the same chromosome and the degree of over‐ or underrepresentation of an expected haplotype measures the extent of LD between a specific pair of alleles. Multilocus patterns of LD are often visualised graphically, revealing local blocks of high LD. LD is generated by mutation but may also be generated and maintained by population processes including selection, drift and admixture. Genomic rearrangements, such as inversions may also influence LD patterns. Recombination overtime acts to reduce LD and this relationship may be used to date alleles.

Key Concepts:

  • Linkage disequilibrium described the nonrandom association between pairs of alleles at different loci.

  • The loci under consideration are typically, but not necessarily, physically linked (on the same chromosome) and the allelic interactions can be described in terms of haplotype or ‘gamete’ frequencies and their deviation from expectation under independence.

  • LD coefficients refer to specific pairs of alleles and are often normalised to minimise their dependence on allele frequencies. Higher‐order multiallelic or multiple‐loci coefficients exist but are complex.

  • Multiple, linked loci typically exhibit blocks of high LD interspersed by areas of higher recombination.

  • De novo mutation generates perfect LD between the mutated site and flanking polymorphic sites. This LD is eroded overtime by recombination, the rate of decay being function of physical distance between the loci. This relationship can be used to date alleles.

  • The presence of four haplotypes (or D′<1) in a two‐locus bi‐allelic system (e.g. a pair of SNPs) implies that at least one recombination event has occurred.

  • LD may be generated and maintained by positive and balancing selection, genetic drift in small populations, admixture and gene flow and genomic rearrangements.

  • LD forms the basis for mapping complex disease association by association.

Keywords: haplotype; gametic phase; mutation; recombination; population processes; association; epistasis; complex disease; HapMap

Figure 1.

Blocks of LD across the human DLG5 gene and its flanking region. Graphical pairwise LD among single nucleotide polymorphisms (SNPs) as output by the software Haploview (Barrett et al., ). SNPs in the gene DLG5 occupy block of strong LD (D′>0.8) as defined by the dark red squares. White square indicates weak LD and the blue squares indicate high D′ values but low LOD scores. Reproduced with permission from Stoll et al., . © Nature Publishing Group.



Abecasis GR and Cookson WO (2000) GOLD – graphical overview of linkage disequilibrium. Bioinformatics 16(2): 182–183.

Ayres KL and Balding DJ (2001) Measuring gametic disequilibrium from multilocus data. Genetics 157: 413–423.

Barrett JC, Fry B, Maller J and Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2): 263–265. Epub 5 Aug 2004.

Bengtsson BO and Thomson G (1981) Measuring the strength of association between HLA antigens and diseases. Tissue Antigens 18: 356–363.

Devlin B and Risch N (1995) A comparison of linkage disequilibrium measures for fine‐scale mapping. Genomics 29: 311–322.

Felsenstein J (1965) The effect of linkage on directional selection. Genetics 52: 349–363.

Gorelick R and Laubichler MD (2004) Decomposing multilocus linkage disequilibrium. Genetics 166: 1581–1583.

Hill WG and Robertson A (1968) Linkage disequilibrium in finite populations. Theoretical and Applied Genetics 38: 226–231.

Hraber P, Kuiken C and Yusim K (2007) Evidence for human leukocyte antigen heterozygote advantage against hepatitis C virus infection. Hepatology 46(6): 1713–1721.

Hudson RR and Kaplan NL (1985) Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics 111: 147–164.

International HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861.

Keinan A and Clark AG (2012) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336: 740–743.

Lewontin RC (1964) The interaction of selection and linkage I. General considerations; heterotic models. Genetics 49: 49–67.

Lewontin RC and Kojima K (1960) The evolutionary dynamics of complex polymorphisms. Evolution 14: 458–472.

Morton NE (1955) Sequential tests for the detection of linkage. American Journal of Human Genetics 7: 277–318.

Morton NE, Zhang W, Taillon‐Miller P et al. (2001) The optimal measure of allelic association. Proceedings of the National Academy of Sciences of the USA 98: 5217–5221.

Nothnagel M, Fürst R and Rhode K (2002) Entropy as a measure of linkage disequilibrium over multilocus haplotype blocks. Human Heredity 54: 186–198.

Schmegner C, Hoegel J, Vogel W and Assum G (2005) Genetic variability in a genomic region with long‐range linkage disequilibrium reveals traces of a bottleneck in the history of the European population. Human Genetics 118: 276–286.

Slatkin M (2008) Linkage disequilibrium – understanding the evolutionary past and mapping the medical future. Nature Reviews Genetics 9: 477–485.

Slatkin M and Rannala B (2000) Estimating allele age. Annual Review of Genomics and Human Genetics 1: 225–249.

Stoll M, Corneliussen B, Costello CM et al. (2004) Genetic variation in DLG5 is associated with inflammatory bowel disease. Nature Genetics 36(5): 476–480.

Weir BS (1996) Genetic Data Analysis II. Sunderland, MA: Sinauer Associates.

Further Reading

Clark AG, Wang X and Matise T (2010) Contrasting methods of quantifying fine structure of human recombination. Annual Review of Genomics and Human Genetics 11: 45–64.

Daly M, Rioux JD, Schaffner SF, Hudson TJ and Lander ES (2001) High‐resolution haplotype structure in the human genome. Nature Genetics 29: 229–232.

Goldstein DB (2001) Islands of linkage disequilibrium. Nature Genetics 29: 109–111.

Jorde JB (2000) Linkage disequilibrium and the search for complex disease genes. Genome Research 10: 1435–1444.

Kruglyak L (1999) Prospects for whole‐genome linkage disequilibrium mapping of common disease genes. Nature Genetics 22: 139–144.

Lewontin RC (1988) On measures of gametic disequilibrium. Genetics 120: 849–852.

Maynard Smith J (1989) Evolutionary Genetics. Oxford, UK: Oxford University Press.

Nordborg M and Tavaré S (2002) Linkage disequilibrium: what history has to tell us. Trends in Genetics 18: 83–90.

Reich DE, Cargill M, Bolk S et al. (2001) Linkage disequilibrium in the human genome. Nature 441: 199–204.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Croucher, Peter JP(Apr 2013) Linkage Disequilibrium. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0005427.pub3]