CLINICAL HANDBOOK OF SCHIZOPHRENIA

6. Genetics 61degree relatives despite the mere doubling of biological relation to the individual withschizophrenia. Furthermore, it was noted that the risk to offspring of two parents withschizophrenia, from whom the affected offspring received all of their genes, was not absolute(~46%).Consistent with modern conceptualizations of schizophrenia as a continuous ratherthan discrete entity, most evidence suggests that family members of an affected patient areat a heightened risk for schizophrenia spectrum conditions, in addition to their increasedliability to schizophrenia. For example, approximately 9% of the relatives of a patientwith schizophrenia will have a psychotic disorder that does not meet criteria for schizophrenia(e.g., schizoaffective disorder or psychosis not otherwise specified). Aggregationof schizotypal personality disorder is also frequently observed in families affected byschizophrenia, with an incidence as high as 14.6% in relatives of a patient with schizophrenia.Despite this powerful evidence, it is important to recognize that familiality does notnecessarily establish heritability. For example, religion and language are familial traits,because all members of the same family often practice the same religion and speak thesame language. These facts do not reflect the transmission of “religion genes” or “languagegenes” through the family, but rather the common environment and upbringingthat those family members share.Twin and Adoption StudiesMost of the twin studies of schizophrenia have supported a genetic contribution to thedisorder. The best evidence from these studies suggests a concordance rate of approximately46–53% for MZ twins and 14–15% for DZ twins. It is interesting to note that theconcordance rate of MZ twins is not twice that of DZ twins, despite the fact that on averagethe former share twice the genetic material of the latter. Instead, the best available evidenceindicates that MZ twins are more than three times more likely than DZ twins toexhibit concordance for schizophrenia, suggesting the possibility of gene–gene interactions(epistasis) in the etiology of the disorder. Furthermore, MZ twins are not 100%concordant for the disease. In fact, based on the differences in schizophrenia concordancebetween MZ and DZ twin pairs, the heritability of the disorder has been estimated at between60 and 70%, whereas most of the remaining liability for the disorder is acquiredthrough environmental factors that are unique to the individual rather than shared byfamily members. In the most compelling adoption study of schizophrenia, Kety, Rosenthal,Wender, and Schulsinger (1968) examined 5,483 Danish children who were adoptedbetween 1923 and 1947, and found that more adoptees who were separated from a biologicalparent with schizophrenia developed schizophrenia or a related disorder than didcontrol adoptees (8.7 and 1.9%, respectively). Thus, it appears that genetic transmissionof schizophrenia risk genes is the major contributor to the familial aggregation of the disorder;however, these observations also highlight the important role of environmentalfactors in its development and expression.Segregation AnalysesThe complexity of schizophrenia inheritance was suggested by the observations of incompleteMZ twin concordance and less than complete transmission of the illness from twoparents with schizophrenia to their offspring, along with the nonlinear relationship betweenrisk and degree of biological relationship to a patient with schizophrenia. Theclearest finding from analyses of the segregation of schizophrenia through extended pedi-