Disease, Genetics of

Genetics is believed to play a role in almost every human disease. Even for diseases traditionally described as environmental, such as tuberculosis and HIV, scientists are discovering that genetics is implicated either in the susceptibility to infection or in the severity of the disease. In some disorders a variation within a single gene is sufficient to cause disease, while in other disorders variations within a gene must interact with the environment and other genes to cause disease. The goal of human medical genetics is to identify all the genes that are involved in human disease and determine how the genes function to cause susceptibility to disease. This knowledge leads to the development of successful therapies that improve the quality of life of affected individuals and their families.

Mendelian and Complex Disorders

Geneticists typically classify genetic disorders into two main categories: Mendelian and complex disorders. Mendelian disorders, such as sickle-cell disease, cystic fibrosis, and Duchenne muscular dystrophy, are usually rare in the general population. These disorders have predictable, recognizable inheritance patterns (such as autosomal dominant and X-linked recessive), and variations in a single gene are sufficient to cause expression of the disorder. Furthermore, only individuals who carry a mutation in the causative gene are at risk for expressing the disorder.

In contrast, complex disorders, such as cardiovascular disease, diabetes, cancers, and psychiatric disorders, are common in the general population. In these disorders, genetics plays a significant role, but the biology of the disease is due to a tangled web of genetic and environmental interactions. Consequently, complex disorders generally do not display the distinct inheritance patterns seen in Mendelian disorders.

While the genetic variation at a single gene may contribute to the overall risk of developing a disease, it is not expected to be sufficient for expression of the disease. A well-known example of this is the association between Alzheimer's disease and the APOE gene. Individuals who carry the "4" allele of the APOE gene have a higher risk and earlier age-of-onset for Alzheimer's disease than those with other alleles. Furthermore, this association is dosedependent. Individuals who have two copies of APOE-4 are at greater risk for developing Alzheimer's disease than individuals who carry one copy of APOE-4 and one copy of a different allele.

How Important Are Genes?

Prior to searching for the genes involved in a disease and determining how those genes work in the various tissues of the human body, there must be clear evidence that genetics is involved in the disease. Genetic analyses are ethically and financially challenging, as well as quite laborious. Geneticists use several methods to evaluate whether or not genetics plays an important role in the etiology of a disorder before they begin a search for a gene. Some of these methods include familial aggregation, recurrence risks, and twin studies.

Familial aggregation can be established by obtaining a thorough family history on study participants. Individuals are simply asked if they have any other family members who have the disease. If individuals with the disease have a higher frequency of affected relatives compared with individuals without the disease, there is evidence of familial aggregation. Although familial aggregation for a disorder is consistent with the involvement of genetics, it may also reflect the presence of a common environmental factor to which all family members have been exposed (such as pesticides or contaminated drinking water).

Relative risk ratios are another method commonly used to determine if there exists a genetic basis to a disease. For example, in cystic fibrosis, an autosomal recessive Mendelian disorder, the risk of disease in the siblings of an affected individual is 1 in 4. The prevalence of the disease is about 1 in 1,600 in the general population.

In 1990 Neil Risch demonstrated that by comparing the risk of a disease occurring in the relatives of an affected individual with the risk of the disease occurring in the general population, one could measure the significance of the genetic component of the disease. The risk ratio, labeled λ_R, where R is the type of relative (such as sibling), is the ratio of the risk of disease in the relative of type R to the prevalence of the disease in the general population. Thus in cystic fibrosis, λ_s = 1/4 ÷ 1/1600 = 400. This means that the risk of developing cystic fibrosis is four hundred times greater for siblings of an affected individual than for an individual in the general population. This clearly demonstrates the effect that genetics plays in the development of cystic fibrosis.

As a general rule, the larger the λ_R, the stronger the genetic component. However, this ratio is extremely sensitive to the frequency of the disease in the general population. The more common the disorder, the lower the λ_R, although this does not necessarily preclude a genetic component to the disorder.

Twin and adoption studies provide a unique opportunity to tease apart the role of genetics and the influence of a common familial environment. Because twins were born at the same time, the environments to which they were exposed are very similar. This holds true for the prenatal environment, and often for the childhood environment, but rarely for adult environments.

Monozygotic (MZ), or identical, twins share 100 percent of their genetic makeup, and dizygotic (DZ), or fraternal, twins share on average 50 percent of their genetic makeup. Twin studies compare disease "concordance" in MZ twins with DZ twins. When both twins in a pair have the disease, the twins are said to be concordant. When one twin has the disease and the other does not, the twins are said to be discordant. If the disorder has a genetic component, then MZ twins will be concordant more often than DZ twins. The difference between the MZ and DZ concordance rates can be used to assess the strength of the genetic component.

In summary, geneticists are finding that some disorders have a large genetic effect and others have a small genetic effect. There are several methods geneticists can use to determine the size of the genetic effect of a disease. However, ultimately, researchers trying to fully understand genetic disorders must identify the genes that are involved and determine their function. The revolution in human genetics, primarily due to the successes of the Human Genome Project, has made and will continue to make an impact on scientists' ability to define the role of genetics in human disease.

see also Alzheimer's Disease; Cancer; Cardiovascular Disease; Complex Traits; Cystic Fibrosis; Diabetes; Epidemiologist; Gene Discovery; Hemoglobinopathies; Inheritance Patterns; Muscular Dystrophy; Triplet Repeat Disease; Twins.

Allison Ashley-Koch