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