Association study of methylenetetrahydrofolate reductase genetic polymorphism 677C&gt;T with schizophrenia in hospitalized patients in population of European Russia

Zhilyaeva, T. V.; Sergeeva, A. V.; Blagonravova, A. S.; Kasimova, L.N.; Kuznetsov, K. V.; Golovanova, V.I.; Shebolkova, T.B.; Korshunova, E.A.

doi:10.1016/j.ajp.2017.11.027

“…Thus, in this study, in patients with schizophrenia, hyperhomocysteinemia caused by deficiency of folate and B12 is confirmed and can be considered a marker of disturbances of vitamin metabolism. This complements the previously obtained data on the genetic background for disturbances of folate metabolism in schizophrenia in the Russian population [ 24 ] confirming that hyperhomocysteinemia in patients is associated with disturbances of B vitamins metabolism, as well as the data available in the literature that hyperhomocysteinemia is an integral marker of folate metabolism disturbances in schizophrenia [ 2 , 4 ]. This is consistent with the data of other authors that the level of Hcy in schizophrenia is higher than in healthy control and is associated with a deficiency of folate and B12 [ 3 ].…”

Section: Discussionsupporting

confidence: 87%

Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

Zhilyaeva

¹

,

Пятойкина

²

,

Bavrina

³

et al. 2021

Schizophrenia Research and Treatment

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A wide range of studies have demonstrated that hyperhomocysteinemia is associated with the risk of schizophrenia, but currently available assumptions about the direct involvement of homocysteine (Hcy) in the pathogenesis of schizophrenia are hypothetical. It is possible that in vivo Hcy is only a marker of folate metabolism disturbances (which are involved in methylation processes) and is not a pathogenetic factor per se. Only one study has been conducted in which associations of hyperhomocysteinemia with oxidative stress in schizophrenia (oxidative damage to protein and lipids) have been found, and it has been suggested that the oxidative stress may be induced by the elevated Hcy in schizophrenic patients. But the authors did not study the level of reduced glutathione (GSH), as well as possible causes of hyperhomocysteinemia—disturbances of folate metabolism. The aim of this work is to analyze the association of Hcy levels with the following: (1) redox markers in schizophrenia GSH, markers of oxidative damage of proteins and lipids, and the activity of antioxidant enzymes in blood serum; (2) with the level of folate and cobalamin (В12); and (3) with clinical features of schizophrenia measured using the Positive and Negative Syndrome Scale (PANSS). 50 patients with schizophrenia and 36 healthy volunteers, matched by sex and age, were examined. Hcy in patients is higher than in healthy subjects ( p = 0.0041 ), and this may be due to the lower folate level in patients ( p = 0.0072 ). In patients, negative correlation was found between the level of Hcy both with the level of folate ( ρ = − 0.38 , p = 0.0063 ) and with the level of B12 ( ρ = − 0.36 , p = 0.0082 ). At the same time, patients showed higher levels of oxidative modification of serum proteins ( p = 0.00046 ) and lower catalase (CAT) activity ( p = 0.014 ). However, Hcy is not associated with the studied markers of oxidative stress in patients. In the group of patients with an increased level of Hcy (>10 μmol/l, n = 42 ) compared with other patients ( n = 8 ), some negative symptoms (PANSS) were statistically significantly more pronounced: difficulty in abstract thinking (N5, p = 0.019 ), lack of spontaneity and flow in conversation (N6, p = 0.022 ), stereotyped thinking (N7, p = 0.013 ), and motor retardation (G7, p = 0.050 ). Thus, in patients with schizophrenia, hyperhomocysteinemia caused by deficiency of folate and B12 is confirmed and can be considered a marker of disturbances of vitamin metabolism. The redox imbalance is probably not directly related to hyperhomocysteinemia and is hypothetically caused by other pathological processes or by an indirect effect of Hcy, for example, on the enzymatic antioxidant defence system (CAT activity), which requires further exploration. Further study of the role of Hcy in the pathogenesis of schizophrenia is relevant, since the proportion of patients with hyperhomocysteinemia is high and correlations of its level with negative symptoms of schizophrenia are noted.

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“…After the removal of overlapping articles and those that did not meet the inclusion criteria ( Fig 1 ), a total of five studies with ADHD including 434 cases and 670 controls [ 2 , 37 – 40 ], 18 studies with BD including 4167 cases and 5901 controls [ 28 – 31 , 41 – 53 ] and 44 studies with SCZ including 16,098 cases and 19913 controls were finally included in our meta-analysis [ 28 – 31 , 42 , 46 , 47 , 52 , 54 – 76 ]. The key characteristics of the studies and NOS scale information are presented in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

Association between MTHFR (677C>T and 1298A>C) polymorphisms and psychiatric disorder: A meta-analysis

Meng

¹

,

Zheng

²

,

Sun

³

et al. 2022

PLoS ONE

2

0

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Recent studies showed that genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) is related to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). However, no consistent conclusion has been determined. This meta-analysis aims to interrogate the relationship between MTHFR gene polymorphisms (677C>T and 1298A>C) and the occurrence of ADHD, BD and SCZ. We retrieved case-control studies that met the inclusion criteria from the PubMed database. Associations between MTHFR polymorphisms (677C>T and 1298A>C) and ADHD, BD and SCZ were measured by means of odds ratios (ORs) using a random effects model and 95% confidence intervals (CIs). Additionally, sensitivity analysis and publication bias were performed. After inclusion criteria were met, a total of five studies with ADHD including 434 cases and 670 controls, 18 studies with BD including 4167 cases and 5901 controls and 44 studies with SCZ including 16,098 cases and 19913 controls were finally included in our meta-analysis. Overall, our meta-analytical results provided evidence that the MTHFR 677C>T was associated with occurrence of BD and SCZ, while the 1298A>C polymorphism was related to ADHD and BD, and additionally the sensitivity analysis indicated these results were stable and reliable. This may provide useful information for relevant studies on the etiology of psychiatric disorders.

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“…These limited case reports gave rise to genetic association studies. Some have shown a genetic association between the MTHFR SNP C667T and schizophrenia [175,[196][197][198][199][200], while other studies in a variety of ethnic groups failed to find such an association [201][202][203]. Gilbody et al [204] concluded that the SNPs C667T and A1298C were only modestly associated with schizophrenia but were somewhat more strongly associated with depression and bipolar disorder.…”

Section: Dysregulation Of the Folate With Psychosis: Mthfr Mutationsmentioning

confidence: 99%

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

Miller

2024

Explor Neuroprot Ther

0

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Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

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Association study of methylenetetrahydrofolate reductase genetic polymorphism 677C>T with schizophrenia in hospitalized patients in population of European Russia

Cited by 12 publications

References 19 publications

Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

Association between MTHFR (677C>T and 1298A>C) polymorphisms and psychiatric disorder: A meta-analysis

Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

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