Multifactorial Inheritance

The multifactorial inheritance model applies to diseases that depend on multiple genetic loci (polygenic) and the additional contribution of environmental factors. Multifactorial diseases are the result of the interplay of multiple environmental risk factors with more than one gene, where these multiple genes are viewed as susceptibility genes. In this model, genes may increase an individual's susceptibility to a particular disease, but the actual expression of the disease depends on the extent to which the individual encounters certain environmental exposures during embryogenesis or throughout his or her life.

Multifactorial diseases include birth defects such as neural tube defects, developmental disabilities such as autism and common adult-onset diseases such as cancer, diabetes mellitus, hypertension, and heart disease. In fact, most geneticists and epidemiologists today believe that the vast majority of diseases are inherited in a multifactorial fashion or their outcomes are influenced by multiple genetic and environmental factors. For example, the phenotypic outcomes in seemingly straightforward single gene or monogenic disorders (such as the classic autosomal recessive disorder, phenylketonuria, or PKU) are increasingly viewed from a multifactorial perspective as a result of new evidence of the complex relationship between genotype and phenotype in PKU.

Multifactorial diseases are labeled non-Mendelian because they do not exhibit the typical pedigree patterns we observe in Mendelian or monogenic disorders that depend on genotypic expression at one genetic locus (e.g., a recessive disorder such as sickle cell disease). An individual is at an increased risk for developing a multifactorial disease if one or more of his or her relatives are affected as well. This risk is greatest among first-degree relatives. However, patterns of multifactorial conditions are less predictable than diseases that are caused by single gene mutations. For example, multifactorial diseases such as asthma, coronary heart disease, and diabetes mellitus are heterogeneous in their etiology. This means that while the final phenotypic outcome of each disease is similar among individuals, each disease is really a group of diseases, with each subtype having variable genetic and environmental causes.

The complex etiology of multifactorial diseases cannot be discussed without a basic understanding of polygenic inheritance. Also known as quantitative inheritance, polygenic inheritance refers to an inheritance pattern in which traits are controlled by two or more genes, each having a small effect on phenotypic expression. These genes contribute some cumulative effect on the phenotype. These effects may be simple, as in a specific gene adding or subtracting from the measured value of the phenotype, or more complex when other genes or environmental factors influence the phenotype. Unlike basic Mendelian traits, polygenic traits show a continuous distribution of phenotypic values in a population and display a bell-shaped, [Page 694]The polygenic threshold theory attempts to explain how the inheritance of continuous traits may be used to conceptualize the occurrence of dichotomous characters such as the presence or absence of a birth defect. According to the polygenic threshold theory, an individual has a certain degree of polygenic susceptibility, or genetic liability, for a particular disease. Theoretically, this susceptibility is normally distributed within populations, with individuals displaying varying degrees of genetic susceptibility. Individuals who exceed the critical threshold value for susceptibility to a disease will develop it, while those below this value will not.

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