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.

Roffman JL, Nitenson AZ, Agam Y, Isom M, Friedman JS, Dyckman KA, Brohawn DG, Smoller JW, Goff DC, Manoach DS.

Source

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.