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PLoS One. 2011;6(9):e25253. doi: 10.1371/journal.pone.0025253. Epub 2011 Sep 28.

A hypomethylating variant of MTHFR, 677C>T, blunts the neural response to errors in patients with schizophrenia and healthy individuals.

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1
Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America. jroffman@partners.org

Abstract

BACKGROUND:

Responding to errors is a critical first step in learning from mistakes, a process that is abnormal in schizophrenia. To gain insight into the neural and molecular mechanisms of error processing, we used functional MRI to examine effects of a genetic variant in methylenetetrahydrofolate reductase (MTHFR 677C>T, rs1801133) that increases risk for schizophrenia and that has been specifically associated with increased perseverative errors among patients. MTHFR is a key regulator of the intracellular one-carbon milieu, including DNA methylation, and each copy of the 677T allele reduces MTHFR activity by 35%.

METHODOLOGY/PRINCIPAL FINDINGS:

Using an antisaccade paradigm, we found that the 677T allele induces a dose-dependent blunting of dorsal anterior cingulate cortex (dACC) activation in response to errors, a pattern that was identical in healthy individuals and patients with schizophrenia. Further, the normal relationship between dACC activation and error rate was disrupted among carriers of the 677T allele.

CONCLUSIONS/SIGNIFICANCE:

These findings implicate an epigenetic mechanism in the neural response to errors, and provide insight into normal cognitive variation through a schizophrenia risk gene.

PMID:
21980405
PMCID:
PMC3182200
DOI:
10.1371/journal.pone.0025253
[Indexed for MEDLINE]
Free PMC Article
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