Interactive effects of COMT Val108/158Met and MTHFR C677T on executive function in schizophrenia.
Schizophrenia is characterized by heritable deficits in executive function. Two common, functional polymorphisms, catechol-O-methyltransferase (COMT) Val108/158Met and methylenetetrahydrofolate reductase (MTHFR) C677T, have separately been associated with executive function performance in schizophrenia. Given the closely related biochemistry of MTHFR and COMT, it is plausible that the T and Val alleles act synergistically to impair executive function. This investigation of 185 outpatients with schizophrenia examined the interactive effects of these two polymorphisms on Wisconsin Card Sorting Task (WCST) performance. Two WCST measures consistently associated with schizophrenia, perseverative errors and inability to generate categories, were contrasted among compound COMT-MTHFR genotype groups. Individuals homozygous for the COMT Val allele who also carried at least one copy of the MTHFR T allele exhibited a significantly higher percentage of perseverative errors than patients in the other genotype groups. While the T allele also exerted a negative effect on category generation, COMT genotype did not contribute to category performance. It is plausible that cumulative effects of the MTHFR T and COMT Val alleles on intracellular methylation profiles and prefrontal dopamine transmission underlie their interactive effect on perseverative errors.
Roffman
Joshua L
JL
Schizophrenia Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. jroffman@partners.org
Weiss
Anthony P
AP
Deckersbach
Thilo
T
Freudenreich
Oliver
O
Henderson
David C
DC
Wong
Donna H
DH
Halsted
Charles H
CH
Goff
Donald C
DC
D000328:Adult; D019943:Amino Acid Substitution / Q000502:physiology; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D019175:DNA Methylation; D004298:Dopamine / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D008954:Models, Biological; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D009435:Synaptic Transmission / Q000235:genetics; D014633:Valine / Q000235:genetics
D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002394:Catechol O-Methyltransferase; D014633:Valine; D004298:Dopamine