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A scientific revolution has occurred in the field of genetics with the advent of molecular biological techniques. Using these techniques, genes influencing risk for many neuropsychiatric diseases have been identified: initially Mendelian single gene conditions such as Huntington disease were resolved; in the last few years complex genetic conditions such as alcohol dependence have yielded specific genes. Some of this work has been facilitated by the study of endophenotypes or biologic vulnerability markers.

Clinical Epidemiology: Twin, Family, and Adoption Studies

Three types of population genetic studies—twin, family, and adoption studies—are conducted to ascertain whether a particular human phenomenon is substantially genetically influenced.

Twin studies are based on the fact that monozygotic (MZ) or identical twins represent a natural experiment in which two individuals have exactly the same DNA sequence for each of their genes. This is in contrast to dizygotic (DZ) or fraternal twins who share 50% of their DNA sequences and are no more genetically similar than any pair of siblings. A phenomenon that is influenced by genetic factors should be more “concordant” (similar) in MZ twins compared to DZ twins.

Family studies can answer three critical questions concerning the inheritance of a disorder:

  • Are relatives of an affected subject at increased risk for the disorder compared to relatives of control subjects?
  • What other disorders may share a common genetic vulnerability with the phenomenon in question?
  • Can a specific mode of inheritance be discerned?

A family study typically begins with a proband or initially ascertained patient, whose relatives are then studied.

Nurnberger Jr JI, Wiegand R, Bucholz K, et al.: A family study of alcohol dependence: Coaggregation of multiple disorders in relatives of alcohol-dependent probands. Arch Gen Psychiatry 2004;61:1246–1256.  [PubMed: 15583116]

Adoption studies: In adoption studies the risk for the disorder may be evaluated in four groups of relatives: the adoptive and biological relatives of affected adoptees and the adoptive and biological relatives of control adoptees. If the disorder is heritable, one should find an increased risk among the biological relatives of affected subjects, compared to the other three groups of relatives. One can also compare risk for illness in adopted-away children of ill parents versus adopted-away children of well parents.

Segregation analysis may be used to determine whether the pattern of illness in families is consistent with a specific mode of transmission. This is most useful for conditions in which a single gene accounts for a substantial portion of the variance. Most major psychiatric disorders do not appear to fall in this category.

Some of the complexities of major psychiatric disorders are as follows:

  • Variable penetrance (some individuals with a genetic predisposition will not manifest the disease)
  • Phenocopies (individuals without a genetic predisposition who manifest the symptoms of the disease)
  • Genetic heterogeneity (more than one type of genetic ...

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