Contributions of Genetic Risk and Fetal Hypoxia to Hippocampal Volume in Patients With Schizophrenia or Schizoaffective Disorder, Their Unaffected Siblings, and Healthy Unrelated Volunteers

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Abstract
OBJECTIVE: The authors examined in an epidemiologic sample the contributions of genetic predisposition and history of fetal hypoxia to hippocampal volume in patients with psychosis. METHOD: High-resolution magnetic resonance imaging was used to measure hippocampal volumes in 72 psychotic probands (60 with schizophrenia and 12 with schizoaffective disorder, ascertained so as to be representative of all such probands in a Helsinki birth cohort), 58 nonpsychotic full siblings of the probands, and 53 demographically similar healthy comparison subjects with no family history of psychosis. RESULTS: Hippocampal volume differences occurred in a stepwise fashion with each increase in genetic load for schizophrenia. The probands had smaller hippocampal volumes than did their full siblings, who in turn had smaller hippocampal volumes than did the healthy comparison subjects. Among the probands, smaller hippocampal volumes were seen in those who experienced fetal hypoxia than in those who did not, a difference not noted within the other two groups. Finally, within the schizophrenic/schizoaffective disorder patients, smaller hippocampal volumes correlated positively with age at onset independent of duration of illness. CONCLUSIONS: These findings suggest that in patients with schizophrenia spectrum disorders, hippocampal volume is influenced in part by schizophrenia susceptibility genes and an interaction of these genes with fetal hypoxia. They further suggest that hippocampal volume in schizophrenia or schizoaffective disorder may be linked to time of disease onset.