MTHFR 677C [rightward arrow] T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val [rightward arrow] Met

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 45; pp. 17573 - 17578
• Main Authors: Roffman, Joshua L, Gollub, Randy L, Calhoun, Vince D, Wassink, Thomas H, Weiss, Anthony P, Ho, Beng C, White, Tonya, Clark, Vincent P, Fries, Jill, Andreasen, Nancy C, Goff, Donald C, Manoach, Dara S
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11-11-2008; National Acad Sciences
• Subjects: Alleles; Biological Sciences; Catechol O-Methyltransferase - genetics; Catechol O-Methyltransferase - metabolism; Cognition; Dopamine - metabolism; Genotype; Genotypes; Humans; Job performance; Magnetic Resonance Imaging; Medical genetics; Methylation; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Methylenetetrahydrofolate Reductase (NADPH2) - metabolism; Polymorphism, Genetic; Prefrontal cortex; Prefrontal Cortex - physiopathology; Schizophrenia; Schizophrenia - genetics; Schizophrenia - physiopathology; Signal Transduction - genetics; United States; Working memory; United States
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0803727105

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val [rightward arrow] Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val [rightward arrow] Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C [rightward arrow] T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.