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

Arch Gen Psychiatry. 2004 Oct;61(10):974-84. doi: 10.1001/archpsyc.61.10.974.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Bipolar Disorder / diagnosis
  • Bipolar Disorder / genetics*
  • Brain / anatomy & histology*
  • Family Health
  • Female
  • Frontal Lobe / anatomy & histology
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Magnetic Resonance Imaging / statistics & numerical data
  • Male
  • Middle Aged
  • Models, Genetic
  • Phenotype*
  • Regression Analysis
  • Schizophrenia / diagnosis
  • Schizophrenia / genetics*
  • Temporal Lobe / anatomy & histology