Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders

Defence Medical Research Institute, Defence Science and Technology Agency, Republic of Singapore.
Psychiatric Genetics (Impact Factor: 1.94). 01/2005; 14(4):227-31. DOI: 10.1097/00041444-200412000-00012
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An elevated homocysteine level has been reported for patients with schizophrenia and depression. We investigated the frequency of the common C667 T variant of the enzyme methylenetetrahydrofolate reductase in controls and patients of Chinese descent.
Controls with no history of mental disorder and patients diagnosed with schizophrenia, bipolar and unipolar disorders were recruited. Genomic DNA from all were genotyped for the C667 T polymorphism by polymerase chain reaction-restriction fragment length polymorphism.
There was no significant difference in genotype distributions or allele frequencies between controls and any of the diagnostic groups, although the frequency of the T allele was higher for all diagnostic groups and for both the male and female genders. When data was analyzed with the minor T allele as dominant, there was an excess of the T-containing genotypes in each of the patient groups compared with controls. For the difference between controls and all cases combined it almost reached statistical significance (P=0.077), with an odds ratio of 1.46 (95% confidence interval, 0.96-2.22).
Although there was no significant association as measured by the P value, the odds ratio and confidence interval provided some evidence of increased risk for individuals with the T-containing genotypes. A minor role for this polymorphism in the pathogenesis of schizophrenia and depression could not be ruled out and would warrant further investigation.

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    • "Regarding MTHFR C677T, several studies have shown an increased risk for MDD in T allele or TT genotype individuals (Arinami et al., 1997; Bjelland et al., 2003; Lewis et al., 2006; Shen et al., 2014), but numerous studies have not found significant associations (Kunugi et al., 1998; Hickie et al., 2001; Tan et al., 2004; Reif et al., 2005; Almeida et al., 2008; Gaysina et al., 2008; Hong et al., 2009; Lizer et al., 2011; Evinova et al., 2012; Lan et al., 2012; Lok et al., 2014). One study (Bousman et al., 2014) reported that bearing the 677CC genotype could increase an individual's probability of remaining depressed in the long term. "
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) genetic variations have been widely studied in major depressive disorder (MDD) and antidepressants outcome. An interaction with catechol-O-methyltransferase (COMT) has also been proved affecting depression. The aim of this study was to clarify the role of the most commonly studied single nucleotide polymorphisms (SNPs) of MTHFR gene in MDD and in treatment response mechanisms, along with the impact of the interaction with COMT. A total of 613 MDD patients, of whom 389 were classified as having treatment resistant depression (TRD), and 463 controls were enrolled. The A1298C, C677T and COMT Val158Met were genotyped. Genetic data were integrated with a transcriptional level analysis in peripheral blood cells (PBCs) and fibroblasts. The A1298C CC homozygotes were more frequent in MDD patients compared to controls in women, increasing twice the genetic risk to develop depression. Moreover this genotype resulted in epistasis with COMT Met carriers in association with MDD. No significant effects were obtained concerning response to treatment. Transcriptional analyses highlighted a strong correlation between the mRNA levels of MTHFR in fibroblasts and COMT genotypes whereas no significant association with MDD was found. PBCs results revealed relevant influences of environmental factors. We did not measure folate and homocisteine levels. This study showed the involvement of A1298C, Val158Met and their interaction in MDD. The transcriptional analyses supported the participation of COMT in the folate pathway, which partakes in the complex network of gene×gene and gene×environment interactions of MDD etiopathogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.
    Journal of Affective Disorders 05/2015; 183. DOI:10.1016/j.jad.2015.05.003 · 3.38 Impact Factor
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    • "As there was no significant association as measured by the P value, the odds ratio and confidence interval provided some evidence of increased risk for individuals with the T-containing genotypes. And the role of this polymorphism in the pathogenesis of schizophrenia and BD could not be ruled out [35]. Chen et al. [36] also found no significant difference in either allele frequencies or genotype distribution between BD patients and controls in their association study in the Chinese population and also in the meta-analysis they have conducted [36]. "
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    ABSTRACT: Objective . Several studies with contradictory results from different cultures about association of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in schizophrenia and bipolar disorders. Little is known about this association in Arab culture and Egypt. So the present study aimed to assess the association of MTHFR C677T polymorphism in bipolar disorder (BD) and schizophrenia in comparison to control group. The association between MTHFR C677T polymorphism and the age at onset in schizophrenia or BD was also studied. Methods . Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were used to examine the genotype and allele frequencies of MTHFR C677T polymorphism in 149 healthy subjects and 134 bipolar and 103 schizophrenia patients. Results . In BD and schizophrenia, there was a higher prevalence of MTHFR C677T polymorphism than healthy subjects. Earlier age at onset was found in patients with BD, carrying one copy of the T allele or CT genotypes but not in patients with schizophrenia. Conclusion . The present findings suggest that the MTHFR C677T polymorphisms are likely to be associated with the risk of developing BD and schizophrenia and influence the age at onset of BD but not the age at onset of schizophrenia.
    BioMed Research International 07/2014; 2014(1):318483. DOI:10.1155/2014/318483 · 2.71 Impact Factor
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    • "Figures 1 and 2 describe the identification, screening, eligibility and inclusion of the identified articles using the searches on SZ and BPD, respectively. A total of 46 articles (33 studies for SZ and 13 for BPD) were eligible, of which eight studies reported ORs for these two disorders (Arinami et al. 1997; Kunugi et al. 1998; Tan et al. 2004; Kempisty et al. 2006, 2007; Jonsson et al. 2008; Arzaghi et al. 2011; El-Hadidy et al. 2013). A total of 38 articles were included in the meta-analysis, 27,060 subjects (11,646 patients and 15,414 controls) with genotyping of MTHFR C677T, and 14,811 subjects (6,265 patients and 8,546 controls) with genotyping of MTHFR A1298C (Arinami et al. 1997; Kunugi et al. 1998; Virgos et al. 1999; Joober et al. 2000; Sazci et al. 2003; Tan et al. 2004; Yu et al. 2004; Reif et al. 2005; Sazci et al. 2005; Vilella et al. 2005; Kempisty et al. 2006; Lee et al. 2006; Philibert et al. 2006; Kempisty et al. 2007; Yang et al. 2007; Jonsson et al. 2008; Muntjewerff et al. 2008; Ozbek et al. 2008; Zhao et al. 2008; Roffman et al. 2008; Betcheva et al. 2009; Chen et al. 2009; Feng et al. 2009; Bouaziz et al. 2010; Garcia-Miss Mdel et al. 2010; Kang et al. 2010; Ye et al. 2010; Zhang et al. 2010; Arzaghi et al. 2011; Ezzaher et al. 2011; Kim et al. 2011; Muntjewerff et al. 2011; Tsutsumi et al. 2011; Zhang et al. 2012; El-Hadidy et al. 2013; Kontis et al. 2013; Zhang et al. 2013; Nishi et al. 2014). "
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    ABSTRACT: Previous studies examining the possible role of the methylenetetrahydrofolate reductase (MTHFR) polymorphisms in the development of schizophrenia (SZ) and bipolar disorder (BPD) have provided inconclusive findings, this meta-analysis was therefore designed to get a more reliable assessment. A total of 38 articles were identified through a search of electronic databases, up to 27 February 2014. Odds ratios (ORs) with 95 % confidence interval (CIs) were calculated using random effects models. Meta-analysis showed that MTHFR C677T was significantly associated with SZ, the highest OR was found for the recessive model (for TT vs. CT + CC: OR = 1.34, 95 % CI: 1.18-1.53); a marginal association of MTHFR C677T with increased risk of BPD has also been found for the recessive model (OR = 1.26, 95 % CI: 1.00-1.59). Subgroup analysis by ethnicity indicated that the significant association with SZ and BPD existed among Asian and African populations, but not for the white. MTHFR A1298C was significant associated with SZ, the highest OR for the dominant model (OR = 1.13, 95 % CI: 1.03-1.24). Subgroup analysis indicated a significant association with SZ existed in Asian populations, not among the white populations and no significant association was detected between the MTHFR A1298C and BPD in all groups. We conclude that MTHFR polymorphism is associated with SZ and BPD among Asian, African populations, but not the white.
    Journal of Neural Transmission 06/2014; 122(2). DOI:10.1007/s00702-014-1261-8 · 2.40 Impact Factor
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