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Key Points

  • Overview:

    • The past 5 years have been a time of tremendous progress in our understanding of the genetic basis of polygenic traits, with over 1100 genomic loci having been associated with over 165 complex (ie, polygenic) traits. While this has led to huge advances in our understanding of the mechanisms of disease, the clinical application of this information to risk prediction has been more limited. The reasons for this are outlined here. Since a detailed discussion of genetic risk for every disease is beyond the scope of this chapter, we focus on a few illustrative examples.

  • Genome-wide association studies (GWAS) have dramatically increased our understanding of the mechanisms of common human diseases.

  • Applying these results to clinical medicine is difficult due to both incomplete heritability and an incomplete understanding of the genetic basis of human disease.

  • Further studies are needed to better understand how genetically based risk prediction can be effectively applied to the management of human diseases. Studies are also needed that address the ethics of genetic disclosure and its psychologic effects on patients.

Basic Definitions and Principles

Modes of Inheritance: Monogenic Versus Polygenic

Monogenic traits are those which are determined by a single gene. Examples include diseases such as cystic fibrosis and Duchenne muscular dystrophy, as well as benign traits such as having attached earlobes. Polygenic traits, in contrast, are the result of many genes. Examples again include both diseases such as type 2 diabetes mellitus, as well as nondisease traits such as stature. Note that polygenic traits, although frequently quantitative (eg, blood pressure or low-density lipoprotein [LDL] cholesterol), can also be binary (eg, coronary artery disease or schizophrenia). For nonquantitative polygenic traits, a threshold model is frequently used to explain modes of inheritance.


In its most simplistic formulation, the variation of any trait can be partitioned into a genetic component (G) and an environmental component (E). Heritability refers to the proportion of trait variation that can be attributed to genetic variation (ie, G/[G + E]), and its value ranges from 0 (ie, no genetic contribution) to 1 (completely genetic). Although the variation of a trait can be directly measured, the heritability must be indirectly inferred. There are many methods for this, but one of the most common is through the comparison of monozygotic and dizygotic twins; if the correlation for the trait among monozygotic twins is higher than that among dizygotic twins, then the trait is more heritable (the interested reader is encouraged to refer to Genetics and Analysis of Quantitative Traits for a further discussion of this method, which is known as Falconer’s formula).

Genome-Wide Association Study

A new method developed in recent years to identify genetic variants that increase or decrease the likelihood of a polygenic trait. In a typical GWAS, one ...

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