In an age when the majority of monogenic human disease genes have been identified, one of the challenges for the coming generation of human geneticists will be to resolve complex polygenic and multifactorial disorders, as human diseases are often caused by a multitude of genetic and environmental factors acting in concert.

The term polygenic can have different meanings, including genetic effects that arise from the interaction of multiple genes. It can be said that polygenic inheritance involves complex traits that are determined by many genes at different loci, without the influence of the environment. Effects of those genes are cumulative, i.e. no single gene is considered to be dominant or recessive to another.

On the other hand, multifactorial inheritance describes a trait whose manifestations are determined by two or more genes, accompanied by environmental factors. These conditions show a definite familial tendency, although the incidence in close relatives of affected individuals is usually in a range from 2 to 4%, compared to the conditions caused by mutations in single genes (25-50%).

Since there is seldom a clear distinction between the two, both of these entities are often considered together. Some geneticists tend to use the term polygenic for any trait whose inheritance is complex, whereas others apply the term multifactorial equally indiscriminately.

Multifactorial and polygenic diseases

A number of single gene disorders are relatively rare when compared to multifactorial and polygenic diseases. Congenital malformations that are thought to have complex multiple interacting causes include congenital heart defects, neural tube defects, pyloric stenosis, cleft palate and congenital hip dysplasia.

Many of these congenital birth defects are explained by a multifactorial threshold model. This assumes that the gene defects for multifactorial traits are normally distributed within the population, with most individuals having too few of them to cause disease. Thus pathological condition will not arise unless there is a genetic liability present that is significant enough to push them past the threshold and move them into the affected range.

Polygenic and environmental factors contribute significantly to chronic, non-communicable diseases such as coronary heart disease, cancer, diabetes mellitus, asthma, gout, schizophrenia and osteoporosis. A genetic component to the disease contributes a certain percent (for schizophrenia it is estimated to be approximately 70%), but no single gene is responsible.

Important concept in the multifactorial genetic disorders is the quantitative trait locus, which is used to map polygenic traits measurable in some quantitative manner. Therefore complex characteristics such as height (normal trait) or diabetes (abnormal trait) are contributed to by a myriad of different genes found on different chromosomes, with an additional effect of the environment.

Counseling for multifactorial disorders

A number of factors can influence the recurrence risk in multifactorial disorders, which should be taken into account when counseling. In general, the recurrence risk is slightly greater for consanguineous parents when compared to those who are unrelated. In other words, multifactorial disorders show a slightly increased incidence in the offspring of consanguineous parents, although not nearly as striking as for autosomal recessive disorders.

If the proband (the first affected family member) is severely affected, then risks to close relatives are greater than if the proband is only mildly affected. If there is more than one affected close relatives, the risks for other relatives are significantly increased.

When the disorder in question is more commonly found in one sex, there is a tendency for recurrence risks to be greater for relatives of the less commonly affected sex. The threshold is often different for men and women for some diseases (e.g. pyloric stenosis affects boys five times more often affected than girls, while congenital dislocation of the hip is about seven times more frequent in women than men).

In conclusion, the carriage of certain combinations of genes is responsible for the occurrence of clinically heterogeneous forms of the disease and treatment effectiveness. Population screening for rare genetic disorders with high penetrance will continue to be a mainstay for genetic screening.