Many common congenital malformations and diseases are caused by a combination of genetic and environmental factors. The term multifactorial inheritance is used to describe conditions that occur due to these multiple factors. In contrast to dominantly or recessively inherited diseases, multifactorial traits do not follow any particular pattern of inheritance in families. Multifactorial conditions do tend to cluster in families, but pedigree analysis does not reveal a specific pattern of affected individuals. Some multifactorial conditions occur because of the interplay of many genetic factors and limited environmental factors. Others occur because of limited genetic factors and significant environmental factors. The number of genetic and environmental factors vary, as does the amount of impact of each factor on the presence or severity of disease. Often there are multiple susceptibility genes involved, each of which has an additive affect on outcome.
Examples of congenital malformations following a multifactorial pattern of inheritance include cleft lip and palate, neural tube defects, and heart defects. Adult onset diseases that follow multifactorial inheritance include diabetes, heart disease,epilepsy and affective disorders like schizophrenia. Many normal traits in the general population follow multifactorial inheritance. For instance, height, intelligence, and blood pressure are all determined in part by genetic factors, but are influenced by environmental factors.
Continuous and discontinuous traits
Some multifactorial traits are considered continuous because there is bell shaped distribution of those traits in the population. These are quantitative traits such as height. Other traits are discontinuous because there is a cutoff or threshold of genetic and environmental risk that must be crossed in order for the trait to occur. An example would be a malformation like a cleft lip, in which the person is either affected or unaffected. In both cases, the genetic and environmental factors that are involved in the occurrence of the condition are referred to as liability.
Pyloric stenosis
An example of a discontinuous multifactorial trait that follows the threshold model is pyloric stenosis. Pyloric stenosis is a narrowing of the pylorus, the connection between the stomach and the intestine. Symptoms of pyloric stenosis include vomiting, constipation, and weight loss. Surgery is often needed for repair. An important genetic factor in the occurrence of pyloric stenosis is a person's sex. The condition is five times more common in males. The liability is higher in women, such that more or stronger genetic and environmental factors are needed to cause the condition in women. Therefore, male first-degree relatives of a female who is affected with pyloric stenosis have a higher risk to be born with the condition than do female first-degree relatives of the same person. This is because the stronger genetic factors present in the family (represented by the affected female) are more likely to cross the lower liability threshold in male family members.
Recurrence risks
Recurrence risks for multifactorial traits are based on empiric data, or observations from other families with affected individuals. Most multifactorial traits have a recurrence risk to first-degree relatives of 2-5%. However, empiric data for a specific condition may provide a more specific recurrence risk. Some general characteristics about the recurrence risk of multifactorial traits include:
The recurrence risk to first-degree relatives is increased above the general population risk for the trait, but the risk drops off quickly for more distantly related individuals.
The recurrence risk increases proportionately to the number of affected individuals in the family. A person with two affected relatives has a higher risk than someone with one affected relative.
The recurrence risk is higher if the disorder is in the severe range of the possible outcomes. For instance, the risk to a relative of a person with a unilateral cleft lip is lower than if the affected person had bilateral cleft lip and a cleft palate.
If the condition is more common in one sex, the recurrence risk for relatives is higher in the less affected sex. Pyloric stenosis is an example of this.
Recurrence risks quoted are averages and the true risk in a specific family may be higher or lower.
It is also important to understand that recurrence risks for conditions may vary from one population to another. For instance, North Carolina, South Carolina, and Texas all have a higher incidence of neural tube defects that other states in the United States. Ireland has a higher incidence of neural tube defects than many other countries.
Neural tube defects
Neural tube defects are birth defects that result from the failure of part of the spinal column to close approximately 28 days after conception. If the anterior (top) portion of the neural tube fails to close, the most severe type of neural tube defect called anencephaly results. Anencephaly is the absence of portions of the skull and brain and is a lethal defect. If a lower area of the spine fails to close,spina bifida occurs. People with spina bifida have varying degrees of paralysis, difficulty with bowel and bladder control, and extra fluid in the brain called hydrocephalus. The size and location of the neural tube opening determines the severity of symptoms. Surgery is needed to cover or close the open area of the spine. When hydrocephalus is present, surgery is needed for shunt placement.
Neural tube defects are believed to follow a multifactorial pattern of inheritance. Empiric data suggests that the risk to first-degree relatives of a person with a neural tube defect is increased 3-5%. The risk to other more distantly related relatives decreases significantly. In addition, it is known that a form of vitamin B called folic acid can significantly reduce the chance for the occurrence of a neural tube defect. Studies have shown that when folic acid is taken at least three months prior to pregnancy and through the first trimester, the chance for a neural tube defect can be reduced by 50-70%. This data suggests that one environmental factor in the occurrence of neural tube defects is maternal folate levels. However, some women who are not folate deficient have babies with open spine abnormalities. Other women who are folate deficient do not have babies with spinal openings. The exact interplay of genetic and environmental factors in the occurrence of neural tube defects is not yet clear. Studies are currently underway to identify genes involved in the occurrence of neural tube defects.
Diabetes
There are two general types of diabetes. Type I is the juvenile onset form that often begins in adolescence and requires insulin injections for control of blood sugar levels. Type II is the more common, later onset form that does not usually require insulin therapy. Both are known to be influenced by environmental factors and show familial clustering. Important environmental factors involved in the occurrence of diabetes include diet, viral exposure in childhood, and certain drug exposures. It is clear that genetic factors are involved in the occurrence of type I diabetes since empiric data show that 10% of people with the condition have an affected sibling. An important susceptibility gene for type I diabetes has been discovered on chromosome 6. The gene is called IDDM1. Another gene on chromosome 11 has also been identified as a susceptibility gene. Studies in mice have indicated that there are probably 12-20 susceptibility genes for insulin dependent diabetes. IDDM1 is believed to have a strong effect and is modified by other susceptibility genes and environmental factors.
Analysis of multifactorial conditions
Genetic studies of multifactorial traits are usually more difficult than genetic studies of dominant or recessive traits. This is because it is difficult to determine the amount of genetic contribution to the multifactorial trait versus the amount of environmental contribution. For most multifactorial traits, it is not possible to perform a genetic test and determine if a person will be affected. Instead, studies involving multifactorial traits strive to determine the proportion of the phenotype due to genetic factors and to identify those genetic factors. The inherited portion of a multifactorial trait is called heritability.
Disease association studies
One method of studying the heritability of multifactorial traits is to determine if a candidate gene is more common in an affected population than in the general population.
Sibling pair studies
Another type of study involves gathering many pairs of siblings who are affected with a multifactorial trait. Researchers try to identify polymorphisms common in the sibling pairs. These polymorphisms can then be further analyzed. They can also study candidate genes in these sibling pairs. Studying individuals who are at the extreme end of the affected range and are thought to have a larger heritability for the trait can strengthen this type of study.
Twin studies
Another approach is to study a trait of interest in twins. Identical twins have 100% of their genes in common. Non-identical twins have 50% of their genes in common, just like any other siblings. In multifactorial traits, identical twins will be concordant for the trait significantly more often than non-identical twins. One way to control for the influence of a similar environment on twins is to study twins who are raised separately. However, situations in which one or both identical twins were adopted out and are available for study are rare.
Linkage analysis and animal studies are also used to study the heritability of conditions, although there are significant limitations to these approaches for multifactorial traits.
Ethical concerns of testing
One of the goals of studying the genetic factors involved in multifactorial traits is to be able to counsel those at highest genetic risk about ways to alter their environment to minimize risk of symptoms. However, genetic testing for multifactorial traits is limited by the lack of understanding about how other genes and environment interact with major susceptibility genes to cause disease. Testing is also limited by genetic heterogeneity for major susceptibility loci. Often the attention of the media to certain genetic tests increases demand for the test, when the limitations of the test are not fully explained. Therefore, it is important for people to receive appropriate pre-test counseling before undergoing genetic testing. Patients should consider the emotional impact of both positive and negative test results. Patients should understand that insurance and employment discrimination might occur due to test results. In addition, there may not be any treatment or lifestyle modification available for many multifactorial traits for which a genetic test is available. The patient should consider the inability to alter their risk when deciding about knowing their susceptibility for the condition. When a person chooses to have testing, it is important to have accurate post-test counseling about the result and its meaning.
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Lucassen, Anneke. "Genetics of multifactorial diseases." In Practical Genetics for Primary Care by Peter Rose and Anneke Lucassen. Oxford: Oxford University Press 1999, pp.145-165.
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