Although sex differences in the expression of schizophrenia have been reported, no study has attempted to explain these differences as a function of sexual dimorphism of the brain. Animal and human studies have demonstrated a normal sexual brain dimorphism. Thus, it is important to understand whether sex differences in the phenotypic expression of schizophrenia reflect the normal sexual brain dimorphism, and/or whether sex is a risk factor for brain abnormalities in schizophrenia beyond normal expectations. This study will best the latter hypothesis using proband data from multiplex families with schizophrenia, i.e. families with multiply ill members, in the Harvard site of the NIMH Genetics Initiative (MH46318). The use of multiplex probands will provide a better test of the effect of sex alone on brain abnormalities, since they are relatively homogeneous with regard to the potentially confounding effects of familial risk factors. 108 DSM-IV schizophrenia probands, primarily siblings from 54 families, systematically ascertained in the Harvard site of MH46318, will undergo structural magnetic resonance imaging (MRI). Diagnostic information on probands has been collected, at no cost to this proposal. 44 normal controls, equally divided by sex and matched, within sex, on age, ethnicity, and parental SES are currently being ascertained in another ongoing study, also at not cost to this proposal. Structural MRI will be analyzed using a semi-automated, topographic landmark-based parcellation system, that goes beyond what has been conducted in the past, by parcellation of the entire brain into 48 topographically-defined brain areas and extensive parcellation of white matter and subcortical nuclei. We will test specific hypotheses about the relationships between sex and structural brain abnormalities in schizophrenia, including asymmetries, using sophisticated analytic models that control for intrafamilial correlation and that use sib-pair analyses. Specific hypotheses about gray and white matter abnormalities include the normally sexually dimorphic hippocampus, amygdala, anterior cingulate, caudate, pallidum, dorsolateral prefrontal cortex, superior temporal gyrus, corpus callosum, and lateral ventricles, and areas not previously considered sexually dimorphic, such as the thalamus. Findings will contribute to understanding whether sex has an etiologic role in the development of schizophrenia.
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