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 epista-

Variation in Gene 1

Variation in

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Gene 2

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Variation in Gene 1

Variation in

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Gene 2

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81

Figure 1B. Here, the risk of developing a disease varies between 0 and 81. It is determined by multiplying the risk (3) for each T a person has at both Gene 1 and Gene 2.

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