MTHFR 677C → T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val → Met

Abstract

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 3 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 3 Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C 3 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 ؋ 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.dopamine ͉ folate ͉ functional MRI ͉ genetics ͉ methylation

Neural Markers of Errors as Endophenotypes in Neuropsychiatric Disorders

“…Several steps in the DA lifecycle rely on methylation reactions regulated by MTHFR (Friso et al, 2002) and each copy of the T allele reduces MTHFR activity by 35% (Frosst et al, 1995). The T allele has been shown to reduce dorsolateral prefrontal cortex fMRI activation during working memory performance in schizophrenia, both on its own, and via epistatic interactions with the low-DA COMT158Val allele, supporting a role of MTHFR in prefrontal DA signaling (Roffman et al, 2008a). There is also indirect evidence linking MTHFR to striatal DA.…”

“…can be surprisingly large. This allows the investigation of substantially smaller sample sizes and makes it possible to detect significant genotype effects in the absence of overt behavioral differences (e.g., Roffman et al, 2008a). For these reasons, the study of genetic mediation using neuroimaging-based endophenotypes holds promise for uncovering susceptibility genes, mechanisms of illness, and targets for intervention (Hariri et al, 2006).…”

Associations of Cortical Thickness and Cognition in Patients With Schizophrenia and Healthy Controls

“…(For additional details about the paradigm, see ref. 39 ). The stimuli and responses were presented during fMRI and collected using E-prime software (E-Prime v1.1; Psychology Software Tools, Inc.).…”

“…The MCIC study of schizophrenia [39][40][41] obtained sMRI and functional MRI (fMRI) scans on a total of 328 subjects from 4 participating sites: Massachusetts General Hospital in Boston (MGH) and the Universities of Iowa (UI), Minnesota (UMN), and New Mexico (UNM). After complete description of the study to the participants, written informed consent was obtained.…”

Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: Evidence for a common genetic vulnerability?

“…Screening for psychiatric symptoms or disorders in control subjects was reported in 29 samples, but not in eight other samples (Arinami et Sazci et al, 2003); information on psychiatric screening of control subjects was not available for two samples (Yu et al, 2004). Matching of control subjects on ethnic group, geographical area, sex and/ or age was performed in twelve samples (Almeida et al, 2005;Chen et al, 2009;Crisan, 2006;Feng et al, 2009;Gaysina et al, 2008;Hernandez Sanchez et al, 2009;Jonsson et al, 2008;Kelly et al, 2004;Roffman et al, 2008;Sazci et al, 2003Sazci et al, , 2005Tan et al, 2004). Genotyping was performed using polymerase chain reaction (PCR) based methods in all studies.…”