Bibliography: Linkage Disequilibrium Analysis

Linkage disequilibrium (LD) is a phenomenon that when two chromosome locations (two markers, two genes, two loci) are so close to each, that there is a lack of historical (ancestral) recombination events in between. This lack of crossing-over has several effects. If one of the location is where the disease gene is, the marker that is in LD with the gene is "hitchhiked" ("dragged along") by the disease gene. Thus the persons affected with the disease tend to have certain marker allele value at this marker.

LD is slightly different from "linkage": two linked markers (two markers "in linkage") lack current -- as versus ancestral -- recombination events. In a pedigree data, we can still see crossing over between two linked markers, with a low frequency. On the other hand, we may rarely see an actual crossing over between two markers that are in LD in the pedigree data. Such crossing over only occurred (rarely) in the past ("historically").

If the disease-causing mutation occurred once in the past in certain individual (a "founder"), the alleles of all nearby "hitchhiked" markers tend to remain what they were in the currently diseased persons. This difference of allele frequency of the "hitchhiked" markers in affected individuals ("cases") and normal individuals ("controls") can be detected by a standard statistical analysis, such as correlation ("association"), x² ("chi-square") test, etc.

A practical difficulty is applying a straightforward association analysis is that inhomogeneity within either the "case" group or the "control" group can introduce spurious positive correlation. This led to the development of family-based association , with the best known example the TDT, or the transmission disequilibrium test.