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Studies concerning genetic association aim to test whether single-locus alleles or genotype frequencies (or more generally, multilocus haplotype frequencies) are different between 2 groups (usually diseased subjects and healthy controls). Genetic association studies are based on the principle that genotypes are measured "directly", i.e. by sequencing the actual genetic code.

The occurrence together in a population, more often than can be readily explained by chance, of two or more traits of which at least one is known to be genetic. This can be between phenotypes, e.g. visible characteristics such as flower colour or height, between a phenotype and a genetic polymorphism, such as a single nucleotide polymorphism, or between two genetic polymorphisms. Association between genetic polymorphisms occurs when there is non-random association of their alleles as a result of their proximity on the same chromosome; this is known as genetic linkage.

Linkage disequilibrium (LD) is a term used in the study of population genetics for the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is not the same as linkage, which describes the phenomenon whereby two or more loci on a chromosome have reduced recombination between them because of their physical proximity to each other. LD describes a situation in which some combinations of alleles or genetic markers occur more or less frequently in a population than would be expected from a random formation of haplotypes from alleles based on their frequencies.

Genetic association studies are performed to determine whether a genetic variant is associated with a disease or trait: if association is present, a particular allele, genotype or haplotype of a polymorphism or polymorphism(s) will be seen more often than expected by chance in an individual carrying the trait. Thus, a person carrying one or two copies of a high-risk variant is at increased risk of developing the associated disease or having the associated trait.

• Case control studies are a classical epidemiological tool. Case-control studies use subjects who already have a disease, trait or other condition and determine if there are characteristics of these patients that differ from those who don’t have the disease or trait. In genetic case-control studies, the frequency of alleles or genotypes is compared between the cases and controls. The cases will have been diagnosed with the disease under study, or have the trait under test; the controls, who are either known to be unaffected, or who have been randomly selected from the population. A difference in the frequency of an allele or genotype of the polymorphism under test between the two groups indicates that the genetic marker may increase risk of the disease or likelihood of the trait, or be in linkage disequilibrium with a polymorphism which does. Haplotypes can also show association with a disease or trait.

One problem with the case-control design is that genotype and haplotype frequencies vary between ethnic or geographic populations. If the case and control populations are not well matched for ethnicity or geographic origin then false positive association can occur because of the confounding effects of population stratification.

Family based association designs aim to avoid the potential confounding effects of population stratification by using the parents as controls for the case, which is their affected offspring. The most commonly used test is the transmission disequilibrium test, or TDT. This measures association (and linkage) in families with observed transmissions of genetic markers from parents to offspring, in a nuclear family termed the trio. Under no association with the disease, the alleles of the genetic marker under test will have an equal chance of being transmitted from a heterozygous parent to the offspring. If, however, one allele increases risk of disease or trait, this allele will be transmitted to the affected offspring more often than expected by chance alone.

A quantitative trait(see *quantitative trait locus) is a measurable trait that shows continuous variation, such as height or weight. Quantitative traits often have a 'normal' distribution in the population. In addition to the case control design, quantitative trait association can also be performed using an unrelated population sample or family trios in which the quantitative trait is measured in the offspring.

There are many computer packages for analysing genetic association, such as UNPHASED and WHAP. However simple genotypic or alleleic association with a dichotomous trait can be measured using the chi-squared test for significance.

• Genetic linkage
• Linkage disequilibrium

Efficiency and power in genetic association studies by Paul I Wde Bakker, Roman Yelensky, Itsik Pe’er, Stacey B Gabriel, Mark J Daly & David Altshuler1 NATURE GENETICS v.37  N.11  November 2005

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