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


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


METHODS
Psychiatric research center.


METHODS
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.


METHODS
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.
McDonald
Colm
C
Division of Psychological Medicine, Institute of Psychiatry, London. c.mcdonald@iop.kcl.ac.uk
Bullmore
Edward T
ET
Sham
Pak C
PC
Chitnis
Xavier
X
Wickham
Harvey
H
Bramon
Elvira
E
Murray
Robin M
RM
D000293:Adolescent; D000328:Adult; D000368:Aged; D001714:Bipolar Disorder / Q000175:diagnosis / Q000235:genetics*; D001921:Brain / Q000033:anatomy & histology*; D005192:Family Health; D005260:Female; D005625:Frontal Lobe / Q000033:anatomy & histology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010641:Phenotype; D012044:Regression Analysis; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics*; D013702:Temporal Lobe / Q000033:anatomy & histology