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Colm McDonald, MB, MRCPsych; Edward T. Bullmore, MB, MRCPsych; Pak C. Sham, MB, MRCPsych; Xavier Chitnis, MSc; Harvey Wickham, MB, MRCPsych; Elvira Bramon, MD; Robin M. Murray, DSc, FMedSci

Arch Gen Psychiatry. 2004;61:974-984.

Context  For more than a century, it has been uncertain whether or not the major diagnostic categories of psychosis—schizophrenia and bipolar disorder—are distinct disease entities with specific genetic causes and neuroanatomical substrates.

Objective  To investigate the relationship between genetic risk and structural variation throughout the entire brain in patients and their unaffected relatives sampled from multiply affected families with schizophrenia or bipolar disorder.

Design  Analysis of the association between genetic risk and variation in tissue volume on magnetic resonance images.

Setting  Psychiatric research center.

Participants  Subjects comprised 25 patients with schizophrenia, 36 of their unaffected first-degree relatives, 37 patients with bipolar 1 disorder who experienced psychotic symptoms during illness exacerbation, and 50 of their unaffected first-degree relatives.

Main Outcome Measures  We used computational morphometric techniques to map significant associations between a continuous measure of genetic liability for each subject and variation in gray or white matter volume.

Results  Genetic risk for schizophrenia was specifically associated with distributed gray matter volume deficits in the bilateral fronto-striato-thalamic and left lateral temporal regions, whereas genetic risk for bipolar disorder was specifically associated with gray matter deficits only in the right anterior cingulate gyrus and ventral striatum. A generic association between genetic risk for both disorders and white matter volume reduction in the left frontal and temporoparietal regions was consistent with left frontotemporal disconnectivity as a genetically controlled brain structural abnormality common to both psychotic disorders.

Conclusions  Genetic risks for schizophrenia and bipolar disorder are associated with specific gray matter but generic white matter endophenotypes. Thus, Emil Kraepelin’s pivotal distinction was neither wholly right nor wholly wrong: the 2 major psychoses show both distinctive and similar patterns of brain structural abnormality related to variable genetic risk.

Author Affiliations: Division of Psychological Medicine (Drs McDonald, Sham, Wickham, Bramon, and Murray) and Neuroimaging Research Group (Mr Chitnis), Institute of Psychiatry, London; and the Brain Mapping Unit, Department of Psychiatry, University of Cambridge and Addenbrooke’s Hospital, Cambridge (Dr Bullmore), England.

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