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Tyrone D. Cannon, PhD; Theo G. M. van Erp, MA; Isabelle M. Rosso, PhD; Matti Huttunen, MD, PhD; Jouko Lönnqvist, MD; Tiia Pirkola, MA; Oili Salonen, MD, PhD; Leena Valanne, MD; Veli-Pekka Poutanen, MSc; Carl-Gustav Standertskjöld-Nordenstam, MD

Arch Gen Psychiatry. 2002;59:35-41.

Background  Cortical gray matter reductions and cerebrospinal fluid (CSF) increases are robust correlates of schizophrenia, but their relationships to obstetric and other etiologic risk factors remain to be established.

Methods  Structured diagnostic interviews, obstetric hospital records, and magnetic resonance imaging scans of the brain were obtained for 64 schizophrenic or schizoaffective patients (representative of all such probands in a Helsinki, Finland, birth cohort), along with 51 of their nonpsychotic full siblings and 54 demographically similar controls without family histories of psychosis.

Results  Fetal hypoxia predicted reduced gray matter and increased CSF bilaterally throughout the cortex in patients (gray matter effect sizes, -0.31 to -0.56; CSF effect sizes, 0.25 to 0.47) and siblings (gray matter effect sizes, 0.33 to 0.47; CSF effect sizes, 0.17 to 0.33), most strongly in the temporal lobe. Effect sizes were 2 to 3 times greater among cases born small for their gestational age. Hypoxia also correlated significantly with ventricular enlargement, but only among patients (effect size, 0.31). In contrast, fetal hypoxia was not related to white matter among patients and siblings, nor to any tissue type in any region among controls. The associations were independent of family membership, overall brain volume, age, sex, substance abuse, and prenatal infection.

Conclusions  Fetal hypoxia is associated with greater structural brain abnormalities among schizophrenic patients and their nonschizophrenic siblings than among controls at low genetic risk for schizophrenia. This pattern of results points to a gene-environment interaction account of the disorder's neurodevelopmental pathogenesis.

From the Departments of Psychology (Drs Cannon and Rosso and Mr van Erp), Psychiatry and Biobehavioral Sciences, and Human Genetics (Dr Cannon), University of California, Los Angeles; the Department of Mental Health, National Public Health Institute of Finland, Helsinki (Drs Huttunen and Lönnqvist and Ms Pirkola); and the Department of Radiology, University of Helsinki (Drs Salonen, Valanne, and Standertskjöld-Nordenstam and Mr Poutanen).

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