C677T Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism in Schizophrenia and Bipolar Disorder: An Association Study in Iranian Population

By Arzaghi, Seyed Masoud; Hossein-Nedhad, Arash et al. | Iranian Journal of Psychiatry, Winter 2011 | Go to article overview

C677T Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism in Schizophrenia and Bipolar Disorder: An Association Study in Iranian Population


Arzaghi, Seyed Masoud, Hossein-Nedhad, Arash, Shariat, Seyed Vahid, Ghodsipour, Alireza, Ghadiri, Mohammad, Shams, Jamal, Iranian Journal of Psychiatry


Objective: The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T is suspected to be a risk factor for psychiatric disorders, but it remains inconclusive whether the MTHFR polymorphism C677T is imputed to vulnerability to schizophrenia and bipolar disorder.

Methods: We prompted impetus to appraise this polymorphism in an Iranian population. Therefore, 90 patients with bipolar disorder type I (BID) , 66 patients with schizophrenia diagnosed according to DSM-IV criteria, and 94 unrelated controls with no history of psychiatric disorders were recruited for this study. Genotype distribution and allelic frequencies of C677T polymorphism were investigated.

Results: We found no robust differences between patients with BID and schizophrenia with control participants either for allele frequencies or genotype distribution of MTHFR C677T polymorphism. However, a trend toward an increased risk for T allele was observed in the BID patients [with odds ratio (OR) of 1.28(CI 95%: 0.8-1.31), p>0.05].

Conclusion: However, the present and some previous studies failed to elucidate possible interaction between MTHFR C677T polymorphism and vulnerability to schizophrenia and bipolar disorder; still some associations have been revealed in performed meta-analyses that warrant further studies.

Keywords: MTHFR, Polymorphism, Schizophrenia, Bipolar disorder type I (BID) (Bipolar disorder)

Iran J Psychiatry 2011; 6: 1-6

The MTHFR reduces 5, 10- methylenetetrahydrofolate to 5- methylenetetrahydrofolate, the main and active circulatory form of folate. 5- Methylenetetrahydrofolate plays a crucial role in onecarbon metabolism and DNA methylation. 5- Methylenetetrahydrofolate is necessary for methylation of homocysteine to methionine, the prerequisite of Sadenosylmethionine (SAM). (1, 2). This product is a great methyl group donor for several methylation reactions in the brain such as catechol-omethyltransferase (COMT) metabolism (2, 3).

Bipolar disorder (BD) is one of the major psychiatric disorders with rigorous life long disability and a great burden on the affected patients and the society. The prevalence of bipolar disorder was estimated to be 0.96 % in a large population based study in Iran (4). Several family, twin and chromosomal studies suggest genetic predisposition as an etiopathogenesis factor for BD (3, 5-9).

Schizophrenia, another serious psychiatric disorder, affects 0.25% of the Iranian population (4), and numerous genetic studies have hitherto revealed noteworthy association (10-15).

The MTHFR gene is located at the end of short arm of chromosome 1 (1p36.3) ,and two common single nucleotide polymorphism (SNPs) affecting enzyme activities have been reported: C677T and A1298C. (2, 16-20). C677T mutation results in substitution of alanin with valine (A222V) and associates with decrease in enzyme activity, hyperhomocysteinemia, premature cardiovascular disease and neural tube defects (17, 3, 20-25). Hyperhomocysteinemia may induce toxic effects on dopaminergic neurons (26). MTHFR dysfunction has been associated with some psychiatric manifestation in more recent studies suggesting possible role in pathogenesis of psychiatric disorders (27). On the other hand, MTHFR C677T polymorphism may be linked to BD and schizophrenia via excitatory amino-acids hypothesis and/or low SAM plasma concentrations (28, 29). Numerous association studies from different societies and racial descents have focused on possible relations between C677T, and either schizophrenia (30-44) or BD (31, 38-40, 44-49), but results have not been consistent.

In the present study, we investigated MTHFR C677T polymorphism in schizophrenic and BID patients and control subjects in Iran.

Materials and Method

The study was performed on an Iranian population with the same ethnical background and included 90 patients with unrelated bipolar disorder type 1 (BID) (51 males and 39 females with Mean±SD age of 35±8 years), 66 unrelated schizophrenic patients (45 males and 21 female with Mean±SD age of 29±4 years) ,and 94 age and sex matched controls. …

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