Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes

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.