A collaborative study led by investigators from Massachusetts General Hospital (MGH) is giving what may be the first look at how interactions between genes underlie a key symptom of schizophrenia, impaired working memory. Functional imaging studies reveal how a combination of common variants in two genes is associated with reduced activity of important brain structures in schizophrenia patients but not in normal controls. The report has been released online in the Early Edition of the Proceedings of the National Academy of Sciences.
"Schizophrenia is a highly genetic disorder, but we are learning that its genetics are not straightforward. In most cases potential risk genes appear to have very small effects on symptoms, making it difficult to attribute clinical findings to particular genes," says Joshua Roffman, MD, of the MGH Department of Psychiatry, the study's lead author. "To amplify some of these subtle effects, we and others are looking how the genes affect brain function, rather than just behavior."
The team which included investigators from the University of New Mexico, University of Iowa and University of Minnesota through the MIND Clinical Imaging Consortium used functional MRI to scan an area of the prefrontal cortex known to be critical to working memory in 79 schizophrenia patients and 75 healthy controls as they completed a memory task. Levels of cortical activity were then analyzed for any association with common variants in two genes: MTHFR, which regulates folate metabolism and has been associated with schizophrenia risk, and COMT, which is involved with dopamine processing during working memory.
Although the schizophrenia-associated variant of MTHFR was found in both patients and controls, when the working memory task become more difficult, weaker cortical function associated with that variant was seen only in the schizophrenia patients, not in controls. While variations in COMT did not influence co
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Massachusetts General Hospital