A Hypomethylating Variant of MTHFR, 677C > T, Blunts the Neural Response to Errors in Patients with Schizophrenia and Healthy Individuals

作者：Roffman Joshua L^*; Nitenson Adam Z; Agam Yigal; Isom Marlisa; Friedman Jesse S; Dyckman Kara A; Brohawn David G; Smoller Jordan W; Goff Donald C; Manoach Dara S

来源：PLos One, 2011, 6(9): e25253.

DOI：10.1371/journal.pone.0025253

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.

• 出版日期2011-9-28