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Complex Traits

Complex Traits

Complex traits are those that are influenced by more than one factor. The factors can be genetic or environmental. This is in contrast to simple genetic traits, whose variations are controlled by variations in single genes. Examples of simple traits include Huntington's disease and cystic fibrosis. Each of these traits is caused by a mutation in a single gene that alters or destroys the function of that gene. There are several thousand disorders caused by single genes, but these are almost always quite rare in the population, often occurring in less than one in five thousand individuals.

Almost any trait that is not simple is considered complex. If there are just a few genes that affect a trait, it may be called oligogenic. If there are many different genes that affect a trait, it may be called polygenic. If other, nongenetic factors are involved, it may be called multifactorial.

Diseases inherited as complex traits are often much more common in the population and include heart disease, Alzheimer's disease, and diabetes. There are many factors that can affect a complex disease. Perhaps most commonly, these traits have multiple genes, where variations in those genes can influence the risk of developing the disease.

How Genes Are Involved in Complex Disease

Because there are multiple factors involved in complex traits, such traits are difficult for scientists to study and even more difficult to understand. This is because the different factors may not all act equally or independently on the trait.

For example, if there are three genes involved in a trait, the simplest hypothesis is that each gene will contribute about one-third of the genetic effect on the trait. If the effect of the variations in the genes can be added together, then this is called an additive effect. However, that is not the only way multiple genes can have an effect. Rather than being added together, the effects of variations in the genes may have to be multiplied together. If this is the case, this is called a multiplicative effect. Both parts of figure 1 show examples of additive and multiplicative effects.

Both additive and multiplicative effects imply that a variation in each gene has an effect and that the overall effect gets larger when additional genes are involved. However, in some cases two or more gene variants may need to occur together before any effect is seen. An example of this is shown in Figure 2. If multiple genetic variants must occur together, then this is called an epistatic interaction. In epistasis, a particular form of one gene must be present for the effect of a second to be felt.

The overall effect of genes on a trait can be even more complicated, because genes may act in combinations of additive, multiplicative, and epistatic ways. For example, if there are six different genes whose variations can influence the risk of developing the disease, Genes 1, 2, and 3 may act additively, Genes 4 and 5 may act multiplicatively, and Gene 6 may act in an epistatic manner with Gene 2. Another level of complexity can occur because different variations within the same gene may act differently. For example one variation (allele ) in Gene 1 may act additively with Gene 2, whereas another may act multiplicatively with Gene 2.

In simple traits, the variations within the gene usually create major changes in the way the gene's product (the protein it codes for) acts. In most cases, these changes (mutations) are considered causative, because having them is enough to cause the disease. In other words, having the mutation is sufficient to get the disease. These are called causative genes. For instance, in Huntington's disease, the presence of the expanded form of the huntingtin gene is sufficient to cause the disease.

In contrast, in complex traits, the variations in any one of the genes are not usually enough to cause the trait. These variations may simply increase (or decrease) the probability of developing the disease. Thus these genes, and the variations within them, are often called susceptibility genes and susceptibility alleles. It is a particular combination of susceptibility alleles across multiple genes, and possibly including environmental factors, that causes a complex disease.

How the Environment Is Involved in Complex Disease

Genes are not the only things that can affect a complex trait. Often environmental factors can also be involved. The type of environmental factors can be very different for different traits. One obvious example of this is lung cancer. Smoking cigarettes greatly increases the risk of developing lung cancer. Smoking also seems to have an effect on other diseases, including some eye diseases (such as age-related macular degeneration). However, not every chronic smoker will develop lung cancer or eye disease: The presence of particular alleles of susceptibility genes is also a risk factor, as discussed below.

Other environmental factors, which may be more difficult to identify directly, can still be identified by measuring other risk factors, such as gender, age, occupation, level of education, use of alcohol, and other measures of lifestyle. For example, the effect of estrogen may not be measured directly, but could be identified by finding an effect of gender on the risk of developing the disease. The strength of an environmental effect may vary by how much exposure a person has to that effect. For example, the number of years someone has smoked or how many cigarettes per day someone smokes may change the effect of exposure to smoke.

Genes and Environmental Factors May Interact

Just as with the genes themselves, which may act independently or together to cause a complex trait, genes and environmental factors may act independently or together to cause a complex trait. The actions can be additive, multiplicative, or epistatic.

One example of a multiplicative effect occurs in lung disease. Some people have a variation in the alpha-antitrypsin gene that moderately increases the chance that they will develop lung disease. However, if individuals with this variation also smoke regularly, they are at a greatly increased risk of getting lung disease, more than just smoking alone or just having the variation alone. Other cancer-related genes include tumor suppressor genes, whose particular alleles can influence the risk of developing breast cancer, for instance.

An Example of a Complex Trait

Alzheimer's disease is characterized by a gradual loss of brain function, usually starting with increasing loss of memory. Four different genes have been identified that can play a role in causing Alzheimer's disease. Rare mutations in each of three different genes (on different chromosomes) can each cause Alzheimer's disease. A common variation in a fourth gene, called ApoE, which occurs in approximately 35 percent of the population, increases the risk of developing Alzheimer's disease about threefold if a person has one copy of the allele (called e4), and about tenfold if they have two copies of the allele.

Taken together, these four genes account for less than half of all the genetic effects in Alzheimer's disease, indicating that additional genes that have not yet been identified are also important. In addition, environmental risk factors can have an effect. For example, taking certain anti-inflammatory medications, such as ibuprofen, reduces the risk of developing Alzheimer's disease, whereas severe head injury increases it.

see also Alzheimer's Disease; Breast Cancer; Cardiovascular Disease; Diabetes; Epistasis; Inheritance Patterns.

Jonathan L. Haines

Bibliography

Haines, Jonathan L., and Margaret A. Pericak-Vance, eds. Approaches to Gene Mapping in Complex Human Diseases. New York: John Wiley & Sons, 1998.

Strachan, Tom, and Andrew P. Read. Human Molecular Genetics, 2nd ed. New York: John Wiley & Sons, 1999.

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