title: Dissociable genetic contributions to error processing: a multimodal neuroimaging study.
abstract: BACKGROUND
  Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.
  
  
  METHODS
  We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.
  
  
  RESULTS
  We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.
  
  
  CONCLUSIONS
  DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Yigal
authors.initials: Y
authors.lastname: Agam
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Vangel
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Roffman
authors.affiliation: Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Patience J
authors.initials: PJ
authors.lastname: Gallagher
authors.affiliation: Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chaponis
authors.affiliation: Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Haddad
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Goff
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Greenberg
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wilhelm
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Center for Human Genetics Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors.forename: Dara S
authors.initials: DS
authors.lastname: Manoach
mesh_terms: D000328:Adult; D000483:Alleles; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D004569:Electroencephalography; D005071:Evoked Potentials / Q000235:genetics*; D005260:Female; D005838:Genotype; D006179:Gyrus Cinguli / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D015225:Magnetoencephalography; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D064847:Multimodal Imaging; D015999:Multivariate Analysis; D059906:Neuroimaging; D009771:Obsessive-Compulsive Disorder / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012438:Saccades / Q000235:genetics / Q000502:physiology; D012559:Schizophrenia / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology
chemical_list: D050638:Receptors, Dopamine D4; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)