Contribution of Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms to Negative Symptoms in Schizophrenia

Schizophrenia Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Biological psychiatry (Impact Factor: 10.26). 02/2008; 63(1):42-8. DOI: 10.1016/j.biopsych.2006.12.017
Source: PubMed


Folate deficiency may contribute to negative symptoms in schizophrenia, but the underlying mechanism remains uncertain. We examined whether the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C functional polymorphisms contribute to negative symptoms.
Outpatients with schizophrenia (n = 200) were evaluated with the Positive and Negative Syndrome Scale (PANSS). Subjects also provided a blood sample for MTHFR genotype and serum chemistries. Comparisons of PANSS symptoms, folate, and homocysteine status were conducted based on genotype.
The 677T allele load was associated with negative symptom severity. Contrary to our expectations, the T allele was also found to be protective against positive symptoms. The A1298C polymorphism did not contribute to negative symptoms, and only weakly to positive symptoms. The specific effects of the C677T polymorphism were confirmed with haplotype analysis. Among patients homozygous for the 667T allele, serum folate levels correlated with negative symptom severity.
Increased MTHFR 677T allele load confers risk for negative symptoms in schizophrenia, while reducing severity of positive symptoms. Further, the biochemical interaction of low serum folate with 677T-variant MTHFR may induce downstream effects salient to the expression of negative symptoms.

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    • "For example, reduced maternal folate intake (St Clair et al., 2005) and increased maternal blood levels of Hcy (Brown et al., 2007) are both associated with an increased risk for schizophrenia. Low blood levels of folate have been reported in patients with schizophrenia, and are associated with clinical manifestation especially in the negative symptom domain (Goff et al., 2004; Roffman et al., 2008). "
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    ABSTRACT: Objective The present study was to examine serum levels of brain-derived neurotrophic factor (BDNF), folate, homocysteine (Hcy), and their relationships with hippocampal volume and psychopathology in drug naïve, first episode schizophrenia. Method Drug naïve, first episode schizophrenia patients and healthy controls were enrolled in the study. Serum levels of BDNF, folate and Hcy were measured using enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassay (ECLIA), and enzymatic cycling method respectively. Hippocampus was parcellated and bilateral hippocampal volumes were measured using FreeSurfer. Results Forty-six patients with drug naïve, first episode schizophrenia (SZ group) and 30 healthy controls (control group) were enrolled. The SZ group had significantly lower serum levels of BDNF and folate, and significantly higher serum levels of Hcy compared with the control group (p = 0.013, p < 0.001, p = 0.003 respectively). There were no significant differences in hippocampal volumes between the two groups (ps > 0.2). Within the SZ group, there were significant positive relationships between serum levels of BDNF and both left and right hippocampal volumes (r = 0.327, p = 0.026; r = 0.338, p = 0.022 respectively). In contrast, such relationships did not exist in the control group. Within the SZ group, there were significant negative relationships between serum levels of folate and PANSS-total scores and PANSS-negative symptom scores (r = 0.319, p = 0.031; r = 0.321, p = 0.030 respectively); and there was a positive relationship between serum levels of Hcy and PANSS-total scores (r = 0.312, p = 0.035). Controlling for potential confounding variables resulted in similar findings. Conclusions Drug naïve, first episode schizophrenia presents decreased serum levels of BDNF, folate and increased serum levels of Hcy, which may play an important role in the neurodevelopmental process and clinical manifestation of schizophrenia.
    Schizophrenia Research 10/2014; 159(1). DOI:10.1016/j.schres.2014.07.033 · 3.92 Impact Factor
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    • "Furthermore, there are studies showing that the C677T polymorphism in the MTHFR gene is associated with an earlier age of schizophrenia onset (El-Hadidy et al. 2013; Vares et al. 2010); however, some authors have not confirmed this finding (Saetre et al. 2011, 2012; Peerbooms et al. 2010). Finally, this polymorphism has been found to influence the development of metabolic syndrome components in response to antipsychotic treatment (Srisawat et al. 2013; Ellingrod et al. 2008, 2012; van Winkel et al. 2010a, b), cognitive performance (Kontis et al. 2013; Roffman et al. 2008a, b, 2011b), grey matter density (Zhang et al. 2013) and the activation of dorsal anterior cingulate cortex (Roffman et al. 2011a), the severity of aggressive behaviours (Dong et al. 2012) and negative symptoms (Roffman et al. 2008c, 2013a), as well as the efficacy of folate supplementation in the treatment of negative symptoms (Hill et al. 2011; Roffman et al. 2013b) in schizophrenia patients. "
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    ABSTRACT: Accumulating evidence indicates that elevated homocysteine (Hcy) level occurs in first-episode schizophrenia (FES) patients. We included 56 FES patients and 53 healthy controls (HC). Plasma level of Hcy was significantly higher in FES patients than HC (p = 0.044). In addition, plasma levels of high-density lipoproteins (HDL) and folate were significantly lower in FES than in HC (p < 0.001). Positive family history of schizophrenia was associated with lower plasma HDL (p = 0.041) and vitamin B12 (p = 0.017), as well as higher level of Hcy (p = 0.017). Patients with FES, who abused cannabis, had higher levels of Hcy (p = 0.017), as well as lower levels of vitamin B12 (p = 0.017) and HDL (p = 0.041). Plasma Hcy negatively correlated with duration of untreated psychosis (r = -0.272, p = 0.042). There was a positive correlation between Hcy level and the severity of negative symptoms (r = 0.363, p = 0.006) and general psychopathology (r = 0.349, p = 0.008) assessed using Positive and Negative Syndrome Scale (PANSS). Vitamin B12 level was negatively associated with the severity of negative symptoms (r = -0.406, p = 0.002), while folate level negatively correlated with general psychopathology score (r = -0.365, p = 0.006) in PANSS. These results indicate that the severity of one-carbon metabolism alterations and HDL deficiency might be associated with family history of schizophrenia and cannabis abuse. Lower vitamin B12 and folate along with elevated Hcy may influence the severity of FES psychopathology.
    Metabolic Brain Disease 03/2014; 29(3). DOI:10.1007/s11011-014-9534-3 · 2.64 Impact Factor
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    • "Results for both the MTHFR gene and the 5-HTT gene had large effect sizes. The MTHFR gene codes for the an enzyme that plays a role in the regulation of intracellular methylation reactions and may influence dopamine signaling (Roffman et al., 2008). The hypofunctional 677T variant of this gene has been associated with increased SZ risk (Gilbody et al., 2007). "
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    ABSTRACT: In light of observed changes in connectivity in schizophrenia and the highly heritable nature of the disease, neural connectivity may serve as an important intermediate phenotype for schizophrenia. However, how individual variants confer altered connectivity and which measure of brain connectivity is more proximal to the underlying genetic architecture (i.e. functional or structural) has not been well delineated. In this review we consider these issues and the relative sensitivity of imaging methodologies to schizophrenia-related changes in connectivity. We searched PubMed for studies considering schizophrenia risk genes AND functional or structural connectivity. Where data was available, summary statistics were used to determine an estimate of effect size (i.e. Cohen’s d). A random-effects meta-analysis was used to consider (1) the largest effect and (2) all significant effects between functional and structural studies. Schizophrenia risk variants involved in neurotransmission, neurodevelopment and myelin function were found to be associated with altered neural connectivity. On average, schizophrenia risk genes had a large effect on functional (mean d=0.76) and structural connectivity (mean d=1.04). The examination of the largest effect size indicated that the outcomes of functional and structural studies were comparable (Q=2.17, p>0.05). Conversely, consideration of effect size estimates for all significant effects suggest that reported effect sizes in structural connectivity studies were more variable than in functional connectivity studies, and that there was a significant lack of homogeneity across the modalities (Q=6.928, p=0.008). Given the more variable profile of effect sizes associated with structural connectivity, these data may suggest that structural imaging methods are more sensitive to a wider range of effects, as opposed to functional studies which may only be able to determine large effects. These conclusions are limited by methodological
    Frontiers in Psychiatry 03/2012; 3:18. DOI:10.3389/fpsyt.2012.00018
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