In this video, Dr. Korf talks about evidence supporting a multifactorial mode of inheritance, models explaining multifactorial inheritance, and the genetics of common disorders.

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Multifactorial Inheritance, by Dr. Bruce Korf. In collaboration with the University of Alabama at Birmingham.

My name is Bruce Korf. I'm a medical geneticist at University of Alabama at Birmingham. This talk will focus on the principles of multifactorial inheritance. We'll look at the evidence that supports a multifactorial mode of inheritance, some of the models that explain multifactorial inheritance, and then talk about what is known about the genetics of common disorders.

The paradigm that underlies the integration of genetics in medical practice is that we're all born with a genetic liability, sometimes overwhelmingly so, causing a genetic disorder like sickle cell anemia. But most of the time, much more subtle. And it requires the passage of time and exposure to environmental factors in order to transition from what might be described as a pre-symptomatic state ultimately to a disease state. The hope is that if we could identify the genes that contribute to this liability, we might be able to help avoid the exposure to environmental factors and reduce the likelihood of transition to disease. Or if that transition should occur, understand better how and why disease has occurred, and perhaps have better approaches to treatment.

The evidence that multifactorial inheritance is occurring is that a trait has a tendency to recur within families more frequently than might be expected due to chance, but on the other hand, does not follow the principles of Mendelian genetics. For example, a 50% recurrence risk for a dominant, or a 25% risk of having affected children if both parents are carriers for a recessive. Multifactorial, as the name implies, involves a combination of the action of multiple genes interacting with one another and/or with environmental factors.

In most cases, the specific genes that underlie multifactorial traits are not known, and genetic counseling for multifactorial traits is based on empirical data. These are fairly typical data for congenital anomalies that are attributed to multifactorial inheritance where you see a recurrence risk in a first degree relative, that is to say where a parent or sibling is affected, is in the range of 3%. And you'll note that the risk dilutes very quickly as one goes to more distant relatives.

What kind of evidence would support multifactorial inheritance? One would consist of identification of familial clustering. Geneticists use the variable lambda to indicate the risk of relatives affected with a trait compared with the population risk. Lambda sub R is the generic case where relatives of type R are compared with the population risk. Lambda sub S is a commonly used variable, in which we're looking at the ratio of the risk in sibs compared with the population risk.

In the case of cystic fibrosis, which is, of course, an autosomal recessive trait, the risk in sibs if both parents are carriers-- that is, if a child has already been born with CF-- would be 0.25, or one in four. The risk in the population, at least of northern European descent, is 0.0004 and hence, lambda sub S is 500, a very high number. For Huntington disease, an autosomal dominant, the risk in sibs, of course, is 0.5. The risk in the population is about 0.0001, so lambda sub S is about 5,000.

The table shows several examples of congenital anomalies or other multifactorial traits, when you see that the lambda sub S is in the tens, as low as 16, as high as 49. Nowhere near as high as the autosomal recessive or autosomal dominant examples that we've shown. But of course, the risk would be one if the risk is the same in sibs as in the general population, which it isn't for these disorders.

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