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.
Medicine EncyclopediaGenetics in Medicine - Part 1Complex Traits - How Genes Are Involved In Complex Disease, How The Environment Is Involved In Complex Disease, Genes And Environmental Factors May Interact