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Approaches to Determining the Genetic Component of a Disease
King et al (1984) described the steps necessary to define the genetic mechanisms involved in a disease or trait many years ago, but those steps are still valid today. First, the evidence for a familial component to the condition must be established. Next, the cause of familial aggregation must be determined. That is, clustering in a disease may result from common environmental factors, rather than genetic factors, and these two hypotheses must be evaluated. Finally, the specific genetic factors must be identified and the manner in which they interact with each other and with environmental factors to contribute to the disease etiology must be defined.
Below, several approaches are presented to evaluate whether or not genes contribute to the etiology of a disease, and to quantitate the contribution of those genes to the disease etiology.
Co‐segregation with Chromosomal Abnormalities and Other Genetic Disorders
While complex disorders generally do not exhibit a recognizable inheritance pattern, occasionally in a subset of patients, a complex disorder will segregate with a cytogenetic abnormality or another known genetic disorder. These associations provide valuable information regarding the location of at least one locus involved in the disease etiology. For example, individuals with trisomy 21, or Down syndrome, have an increased risk for developing Alzheimer disease. This increased risk is due to amyloid plaques resulting from an increased dosage of the amyloid precursor protein (APP) (Rumble et al. 1989). Thus, it was not surprising to find that a subset of families with early‐onset Alzheimer disease are linked to chromosome 21 and segregate mutations in the APP gene (St George‐Hyslop et al. 1987; Goate et al. 1991). Another example of co‐segregation of a complex disease and cytogenetic abnormality is the association between autistic disorder and 15q11‐q13 abnormalities. There are numerous examples of isolated patients with autistic disorder and duplications or inversions involving 15q11‐q13 (Wolpert et al. 2000). In many cases, the de novo rearrangements are thought to be maternal in origin (Lindgren et al. 1996). In addition, in the absence of these cytogenetic abnormalities, families with two or more individuals exhibiting autistic disorder display evidence for linkage (Philippe et al. 1999; Bass et al. 2000) and linkage disequilibrium (Cook, Jr. et al. 1998; Martin et al. 2000a; Menold et al. 2000) in this region. Although as yet no gene has been identified, the convergence of cytogenetic, linkage, and association data suggest that a locus involved in susceptibility to autistic disorder is located at 15q11‐q13.
Familial Aggregation
One of the characteristics of a genetic disorder is that it aggregates, or clusters, within families. If familial clustering of a disorder is observed, there are several approaches described below to determine if this observation is statistically significant. However, keep in mind that familial clustering may also be due to a common familial environment or simply due to chance. So, while statistical evidence of familial clustering may support the involvement of genetics in the disorder under investigation, it will be necessary to identify the underlying genes to confirm this.
Family History Approach
In this approach, one ascertains the presence or absence of family history in study participants (with and without the condition) and then tests for statistically significant associations between family history and the condition. Khoury et al. (1993) defines three variations on this approach, depending on the level of detail obtained on the relatives. The Abbreviated Family History Approach involves simply questioning the study participants on the presence or absence of the condition in other family members. This method is by far the fastest and cheapest, but also the most susceptible to misclassification because no effort is made to confirm the participant responses. That is, the investigator is relying on the accuracy of the informant’s memory or perception of the family members, rather than directly observing the condition in the relatives. The Detailed Family History Approach requires the investigator to obtain detailed information regarding disease status (including age of onset) and demographic characteristics on each family member. This is the approach routinely utilized in genetic studies. Because the information requested on each family member is more detailed, there is less likelihood of misclassification as with the abbreviated approach. Finally, one can examine and/or interview the relatives directly. This is referred to as the Family Study Approach. Often in this approach, medical records are also reviewed in order to confirm the presence or absence of the condition in the relatives. While time‐consuming and more expensive, this approach certainly provides the most accurate information regarding the family history of a trait.
Once the necessary information has been collected, there are several methods to test for statistically significant association between family history and the condition. If the study design is case‐control, the presence or absence of family history may be treated as a “risk factor” for disease, and the standard epidemiologic 2 × 2 table may be used:
| Family history | ||
|---|---|---|
| Disease in study participant | + | − |
| + | a | b |
| − | c | d |
From here, an odds ratio may be calculated:
(3.1)
The odds ratio derived here is then a measure of the association between family history and the condition. In this case, the odds ratio is the odds of having a positive family history in individuals with the condition compared with the odds of having a positive family history in individuals who are unaffected. This is not to be confused with a risk ratio, which is a prospective measure with respect to an individual’s affection status. That is, the risk ratio is the ratio of the incidence of the condition in individuals with a positive family history compared with those who have a negative family history. However, when the incidence of the condition is low, the odds ratio should closely approximate the risk ratio (Rothman and Greenland 1998).
In keeping with the epidemiologic approach, one can also measure the amount of the disease that can be “attributed” to the presence of a positive family history. This in effect provides information regarding what proportion of the disease is due to genetic causes. There are several methods for calculating attributable fractions, depending on what information is available. Khoury et al. (1993) reviews three of these formulas (Levin 1953; Kelsey et al. 1986; Miettinen 1974) in their book. The Miettinen formula is given below:
Example of Calculating Attributable Fraction
