The basis of many single-gene diseases has already been demonstrated at the protein and the DNA levels by the approaches of biochemical and molecular genetics. In addition, cytogenetics has revealed the chromosomal basis of a small but growing number of significant disorders. Among genetic phenotypes in general, however, single-gene or cytogenetic defects are greatly outnumbered by common disorders that appear to run in families but are neither single-gene nor chromosomal in origin. These disorders, which are still for the most part poorly understood genetically, are said to show multifactorial inheritance, indicating that they are caused by multiple factors, both genetic and, in many cases, environmental. Many congenital malformations show multifactorial inheritance. Other multifactorial disorders, in which the role of environment appears to be relatively large and the underlying etiology may be heterogeneous and complex, appear as common disorders of adult life.
Multifactorial inheritance is defined as inheritance by a combination of genetic factors and in some cases also nongenetic factors, each with only a relatively small effect. The term polygenic inheritance has a more restricted meaning, assuming inheritance hy a large number of genes with small, equal, additive effects, and in this formal sense it may not apply to any human disorder. Traits are sometimes loosely called polygenic when they are caused by multiple genes with no obvious environmental component, but in actual experience it is often hard to judge whether environment plays any causative role.
Multifactorial disorders recur within families, but they do not show any particular pedigree pattern in an individual family. Genetically, they have common characteristics that allow estimation of their multifactorial background and estimation of recurrence risks for an individual family may be larger or smaller than the average.
Consider the following genetic aspects of three different classes of multifactorial traits:
* Many normal characteristics have multifactorial inheritance and are characterized by continuous variation. For these characteristics, an "abnormal" phenotype is simply an extreme variant of the normal range; examples include many cases of nonspecific mental retardation and of unusually tall of short stature.
* A second group of multifactorial disorders is made up of common single congenital malformations, in which there appears to be underlying continuous variation in liability to a particular disorder, but there is no clinical effect until the patient's liability exceeds a "threshold" for the abnormal phenotype. These are usually known as multifactorial threshold traits.
* The third group comprises the common disorders of adult life that make up a large part of clinical medicine, such as coronary artery disease, diabetes mellitus, hypertension, obesity, and most forms of cancer, as well as common psychiatric illnesses, such as manic-depressive psychosis and schizophrenia. Environmental factors are considered to play a large part in these disorders, even though the role of genetics in their etiology is undeniable. In a sense, common disorders of adult life can also be considered threshold traits, but because of the complexity of the risk factors that can lead to them, they are regarded instead as a separate class.