A series of family and adoption studies has provided compelling evidence that schizophrenia is a substantially heritable disorder. While little controversy exists over the significance of genetic factors, the precise mode of inheritance and the nature of the genetic diathesis remain to be determined. One of the more promising approaches to resolving these issues is to study the well family members of patients with schizophrenia. Since schizophrenia has a nontrivial, heritable component, a portion of such unaffected relatives may exhibit neuroanatomical abnormalities associated with familial risk for the disorder. These so-called """"""""endophenotypic"""""""" markers are likely to be closer to the mechanism of gene action and may ultimately be used to facilitate genetic linkage studies and the design of prophylactic interventions. Perhaps the most powerful extension of this logic is the discordant monozygotic twin paradigm. Because these individuals share a common genome, this approach affords the unique advantage of identifying brain abnormalities that can be confidently attributed to environmental factors and/or the presence of the disease process. In this vein, I am proposing to examine data from a structural magnetic resonance imaging study of normal and discordant monozygotic twins to determine whether distinct patterns of cerebral pathology are associated with disease and vulnerability-specific components of schizophrenia. I will also combine quantitative MRI data with prospectively-obtained obstetric and birth records to assess the contribution of perinatal complications to differences in brain structure between discordant twins.
