Intermediate biological phenotypes in the search for schizophrenia gene
Dr. Daniel R. Weinberger
National Inst. Mental Health, Clinical Brain Disorders Branch,
Bethesda, MD, USA, Presenter

Functional brain impairments of cortical information processing revealed by fMRI and magnetic resonance spectroscopy are considered intermediate phenotypes of schizophrenia. Functional polymorphisms of the COMT gene affect fMRI findings. Intermediate phenotypes revealed by fMRI and magnetic resonance spectroscopy may be important for understanding biological effects of genes in schizophrenia.

Intermediate phenotypes represent biological traits associated with genetic risk for complex diseases such as schizophrenia. Evaluating intermediate phenotypes may be useful in genetic studies of schizophrenia because diagnostic symptoms of schizophrenia represent complex phenomena substantially affected by non-genetic abnormalities. The validity of studying intermediate phenotypes in schizophrenia assumes that
 (1) susceptibility genes for schizophrenia can produce measurable phenotypes;
 (2) intermediate phenotypes are distinguishable from diagnostic symptoms of schizophrenia;
 (3) genetic architecture is simpler relative to schizophrenia; and
 (4) susceptibility alleles for intermediate phenotypes are risk alleles for schizophrenia.
Potential intermediate phenotypes of schizophrenia include personality, eye movement, cognitive/neurophysiological deficits, electrophysiological responses, and structural, functional and chemical brain findings. Dr. Weinberger used fMRI to study brain function during cognitive and psychomotor performance tasks, and examined relationships between his findings and functional polymorphisms of the gene that codes for catechol-O-methyl-transferase (COMT).

The fMRI findings during hand sequential motor tasks showed that functional lateralization of the motor cortex was significantly different between controls and a combined group of patients and their unaffected siblings. Moreover, fMRI-demonstrated cortical inefficacy of information processing during working memory differed between controls and unaffected siblings. Patients and their unaffected siblings also showed low hippocampal NAA. fMRI findings during working memory differed among three different genotypes of the COMT gene, which affects synaptic dopamine concentrations in prefrontal cortex.

Dr. Weinberger believes that intermediate phenotypes related to cognitive processing during working memory may help identify a susceptibility gene for schizophrenia.


Reporter: Hiroshi Yoneda, M.D.

 

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