Genetic association
Encyclopedia
Genetic association is the occurrence, more often than can be readily explained by chance, of two or more traits in a population of individuals, of which at least one trait is known to be genetic.
Studies of genetic association aim to test whether single-locus alleles or genotype frequencies (or more generally, multilocus haplotype
frequencies) differ between two groups of individuals (usually diseased subjects and healthy controls). Genetic association studies are based on the principle that genotypes can be compared "directly", i.e. with the sequences of the actual genome
s.
(SNP), 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 is 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.
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
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(TDT) and haploid-relative-risk
(HRR). Both measure association of genetic markers in nuclear families by transmission from parent to offspring. If an allele increases the risk of having a disease then that allele is expected to be transmitted from parent to offspring more often in populations with the disease.
) 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.
Studies of genetic association aim to test whether single-locus alleles or genotype frequencies (or more generally, multilocus haplotype
Haplotype
A haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
frequencies) differ between two groups of individuals (usually diseased subjects and healthy controls). Genetic association studies are based on the principle that genotypes can be compared "directly", i.e. with the sequences of the actual genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
s.
What is genetic association?
Genetic association can be between phenotypes, such as visible characteristics such as flower colour or height, between a phenotype and a genetic polymorphism, such as a single nucleotide polymorphismSingle nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
(SNP), 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
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
.
Linkage disequilibrium
Linkage disequilibrium
In population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is also referred to as to as gametic phase disequilibrium , or simply gametic 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 is 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 designs
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 do not 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
Population stratification
Population stratification is the presence of a systematic difference in allele frequencies between subpopulations in a population possibly due to different ancestry, especially in the context of association studies...
.
Family based designs
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. Two similar tests are used, the transmission disequilibrium testTransmission disequilibrium test
The transmission disequilibrium test was proposed by Spielman, McGinnis and Ewens as a family-based association test for the presence of genetic linkage between a genetic marker and a trait...
(TDT) and haploid-relative-risk
Haploid-relative-risk
Haploid-relative-risk is a family based method for determining gene allele association to a disease. Nuclear families with one affected child are sampled using the parental haplotypes not transmitted as a control. While similar to genotype relative risk , HRR provides a solution to the problem of...
(HRR). Both measure association of genetic markers in nuclear families by transmission from parent to offspring. If an allele increases the risk of having a disease then that allele is expected to be transmitted from parent to offspring more often in populations with the disease.
Quantitative trait association
A quantitative trait (see quantitative trait locusQuantitative trait locus
Quantitative traits refer to phenotypes that vary in degree and can be attributed to polygenic effects, i.e., product of two or more genes, and their environment. Quantitative trait loci are stretches of DNA containing or linked to the genes that underlie a quantitative trait...
) 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.
Statistical programs of association analysis
There are many computer packages for analyzing genetic association, such as UNPHASED, WHAP, FBAT, Merlin, PLINK, and Golden Helix's Software. However simple genotypic or alleleic association with a dichotomous trait can be measured using the chi-squared test for significance.See also
- Genetic epidemiologyGenetic epidemiologyGenetic epidemiology is the study of the role of genetic factors in determining health and disease in families and in populations, and the interplay of such genetic factors with environmental factors...
- Genetic linkageGenetic linkageGenetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
- Linkage disequilibriumLinkage disequilibriumIn population genetics, linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. It is also referred to as to as gametic phase disequilibrium , or simply gametic disequilibrium...
- Personality genetics
External links
- A list of computer programs for genetic analysis including genetic association analysis
- Golden Helix SNP & Variation Suite: Software package for population and family-based genetic association analysis
- GWAS Central - a central database of summary-level genetic association findings