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: 2.27). 01/2005; 14(4):227-31. DOI: 10.1097/00041444-200412000-00012
Source: PubMed

ABSTRACT 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 · 3.71 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 · 2.87 Impact Factor
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    • "Country Ethnic group Cases Controls MTHFR SNP Schizophrenia Arinami, 1997 Japan Asian 297 419 C677T Kunugi, 1998 Japan Asian 343 258 C677T Virgos, 1999 Spain White 210 452 C677T Joober, 2000 Canada White 105 90 C677T Sazci, 2003 Turkey White 130 226 C677T A1298C Tan, 2004 Singapore Asian 236 120 C677T Yu, 2004 Scotland White 426 628 C677T A1298C China Asian 230 251 C677T A1298C Muntjewerff, 2005 Netherlands White 254 414 C677T Sazci, 2005 Turkey White 297 341 C677T A1298C Vilella, 2005 Spain White 234 392 C677T A1298C Kempisty, 2006 Poland White 200 300 C677T Lee, 2006 Korea Asian 235 235 C677T A1298C Philibert, 2006 USA White 200 359 C677T Crisan, 2006 Romania White 93 85 C677T A1298C Kempisty, 2007 Poland White 200 300 A1298C Jonsson, 2008 Norway White 163 177 C677T A1298C Denmark White 419 1006 C677T A1298C Sweden White 258 293 C677T A1298C Roffman, 2008 USA White 79 75 C677T Mavros, 2008 Romania White 44 35 C677T A1298C Feng, 2009 China Asian 123 123 C677T Betcheva, 2009 Bulgaria White 185 184 C677T A1298C Garcia-Miss, 2010 Mexico White 105 108 C677T Bipolar disorder Arinami, 1997 Japan Asian 40 419 C677T Kunugi, 1998 Japan Asian 143 258 C677T Tan, 2004 Singapore Asian 167 120 C677T Reif, 2005 Germany White 92 284 C677T A1298C Kempisty, 2006 Poland White 200 300 C677T Kempisty, 2007 Poland White 200 300 A1298C Jonsson, 2008 Norway White 117 177 C677T A1298C Ozbek, 2008 Turkey White 197 238 C677T A1298C Chen, 2009 China Asian 501 461 C677T Yosifova, 2009 Bulgarian White 94 184 A1298C Depressive disorder Arinami, 1997 Japan Asian 32 419 C677T Kunugi, 1998 Japan Asian 71 258 C677T Hickie, 2001 Australia Not reported 47 21 C677T Bjelland, 2003 Norway Not reported 243 8944 C677T Tan, 2004 Singapore Asian 88 120 C677T Kelly, 2004 UK Not reported 100 100 C677T Reif, 2005 Germany White 45 284 C677T A1298C Almeida, 2005 Australia White 42 198 C677T Chen, 2005 Taiwan Asian 39 20 C677T Lewis, 2006 UK White 545 2942 C677T Almeida, 2008 Australia White 513 3239 C677T Gaysina, 2008 UK White 1222 835 C677T Slopien, 2008 Poland Not reported 83 89 C677T Yuan, 2008 China Asian 116 80 C677T Kim, 2009 South Korea Asian 101 631 C677T Hong, 2009 USA White 178 85 C677T Hernadez-Sanchez, 2009 Spain White 21 21 C677T O.L.J. Peerbooms et al. / Brain, Behavior, and Immunity xxx (2011) xxx–xxx 5 "
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    ABSTRACT: Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.
    Brain Behavior and Immunity 12/2010; 25(8):1530-43. DOI:10.1016/j.bbi.2010.12.006 · 6.13 Impact Factor
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