Complex Genetic Disease: Polygenic and Multifactorial Inheritance
In chromosomal and mendelian (single-gene) disorders, genetic analysis of phenotypic, biochemical, or molecular par ameters is imperative. However, a simple mode of inheritance cannot be assigned and a recurrence risk cannot be predicted for many common, normal characteristics or disorders for which genetic variability clearly exists. Such traits as stature, refractive error, intraocular pressure (IOP), central corneal thickness, and iris color are usually distributed as a continuous variation over a wide range without sharp distinction between normal and abnormal phenotypes. This normal distribution contrasts with the bimodal curve (or trimodal curve in codominant models) noted for conditions transmitted by a single gene. Such conditions are often termed polygenic, implying that they result from the operation of multiple collaborating genes, each with rather minor additive effects. Many of these common genes with small effect have been identified through GWAS. With the exception of AMD, the discovered genes account for only a small percentage of the genetic effect for the traits and diseases investigated.
The term multifactorial inheritance denotes a combination of genetic and environmental factors in the etiology of disease without specifying the nature of the genetic influence. Examples of disorders involving these factors in humans include refractive error, glaucoma, and AMD.
Counseling for recurrence may be difficult in this type of inheritance. Ideally, empirical data are summarized from exhaustive analyses of similarly affected families in the population. In general, the risk is intermediate between population risk and mendelian risk. For example, the population risk for primary open-angle glaucoma (POAG) is 2%–3%, whereas the risk for glaucoma in families with severe myocilin mutations is near 50%. The risk for first-degree relatives of POAG patients is approximately 20%. The more severe the abnormality in the index case, the higher the risk of recurrence of the trait in relatives, presumably because either a greater number of deleterious genes are at work or a fixed population of more harmful genes exists. The risk of recurrence in future children is increased when more than one member of a family is affected, which is not true for mendelian disorders. Such observations have been offered for various forms of strabismus, glaucoma, and significant refractive errors.
Finally, if the malformation or disorder has occurred in both paternal and maternal relatives, the recurrence risk is distinctly higher because of the sharing of multiple unspecifiable but potentially harmful genes in their offspring.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.