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


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.

SUBMITTER: Roffman JL 

PROVIDER: S-EPMC3182200 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Publications

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

Roffman Joshua L JL   Nitenson Adam Z AZ   Agam Yigal Y   Isom Marlisa M   Friedman Jesse S JS   Dyckman Kara A KA   Brohawn David G DG   Smoller Jordan W JW   Goff Donald C DC   Manoach Dara S DS  

PloS one 20110928 9


<h4>Background</h4>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  ...[more]

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