Family Studies in Genetics

Analysis of Aggregation or Clustering

One of the first questions that investigators need to ask when considering genetic studies of a disease or some other trait of interest is ‘What is the evidence that inherited genetic variation has an important influence on the trait?’ A necessary but not sufficient condition required to demonstrate the importance of genetic variation is the occurrence of familial aggregation of the trait. We know from the simple rules of Mendelian inheritance that family members tend to share genes in common. For example, siblings share 50% of their genes inherited identical by descent from their parents, and cousins share 12.5% of genes inherited from their common grandparents. Therefore, if genetic variation really is important for the development of a disease (incidence) or its severity, then we would expect to find the disease co-occurring or ‘clustering’ among family members more often than among randomly drawn unrelated individuals in the population. One way this is often formally tested in research studies is to compare the frequency of disease in relatives of persons with the disease compared with the frequency found in relatives of matched healthy controls. If disease frequency is not at all elevated in relatives of cases, then it is unlikely that most cases of the disease in the population have a substantial genetic basis. On the other hand, familial aggregation of disease is [Page 384]evidence that the trait has a genetic basis but still does not constitute definitive proof. This is because in addition to sharing genes, family members also usually share similar environments (diet, exposure to toxins, etc.), and it is possible that the aggregation of disease in relatives is caused by their common environments rather than by shared genes. Investigators can measure environmental exposures that are suspected to be risks for the disease in cases, in controls, and in their relatives and attempt to statistically adjust for these effects in data analyses. Alternatively, if the disease is sufficiently common, studies of monozygotic and dizygotic twin families offer a very powerful design that can provide very powerful capability to distinguish between environmental and genetic causes of variationindiseaserisk.

For some forms of very severe single-gene (Mendelian) disorders there may not be a positive family history if transmission is dominant and clinical symptoms onset at a young age. People with such diseases are unlikely to reproduce so patients with the disease frequently have arisen via a new mutation not present in their ancestors. On the other hand, with recessive diseases, the parents, not surprisingly, usually do not know that they are carriers for the recessive mutation and the disorder may be new to the family. An exception to this rule is for recessive diseases occurring among cultures with consanguinity (e.g., first-cousin marriages) where occurrence of the disease may not be surprising. Studies of consanguineous families can be very useful for gene-mapping studies.

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