Methylenetetrahydrofolate Reductase and Psychiatric Diseases

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2018 Nov 7

PMID 30397195

Citations 54

Authors

Lin Wan

Yuhong Li

Zhengrong Zhang

Zuoli Sun

Yi He

Rena Li

Affiliations

Soon will be listed here.

Abstract

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for the critical process of one-carbon metabolism involving folate and homocysteine metabolisms. It is known that some polymorphism of MTHFR would result in reduction of MTHFR enzyme activity as well as DNA methylation process, later shown to have significant impacts in various psychiatric diseases. However, it is unclear whether the polymorphism of MTHFR could be an independent or an add-on risk factor for specific psychiatric symptoms, such as anxiety, depression, positive, or negative symptoms of schizophrenia, or acts as risk factor for specific psychiatric disorders, such as schizophrenia, major depression, autisms, and bipolar disorders. It is also understudied on whether folate supplements could be an effective treatment for psychiatric patients with defect MTHFR activity. In this review, we not only gathered the most recent discoveries on MTHFR polymorphism and related DNA methylation in various psychiatric disorders, but also highlighted the potential relationships between MTHFR activity and implication of folate-related function in specific mental diseases.

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References

Song B, Ai J, Kong X, Liu D, Li J . Aberrant DNA Methylation of P16, MGMT, and hMLH1 Genes in Combination with MTHFR C677T Genetic Polymorphism in gastric cancer. Pak J Med Sci. 2014; 29(6):1338-43. PMC: 3905372. DOI: 10.12669/pjms.296.3711. View

Gokcen C, Kocak N, Pekgor A . Methylenetetrahydrofolate reductase gene polymorphisms in children with attention deficit hyperactivity disorder. Int J Med Sci. 2011; 8(7):523-8. PMC: 3167178. DOI: 10.7150/ijms.8.523. View

Klengel T, Pape J, Binder E, Mehta D . The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology. 2014; 80:115-32. DOI: 10.1016/j.neuropharm.2014.01.013. View

da Silva T, Ravindran A . Contribution of sex hormones to gender differences in schizophrenia: A review. Asian J Psychiatr. 2015; 18:2-14. DOI: 10.1016/j.ajp.2015.07.016. View

Kempisty B, Mostowska A, Gorska I, Luczak M, Czerski P, Szczepankiewicz A . Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett. 2006; 400(3):267-71. DOI: 10.1016/j.neulet.2006.02.055. View

Yamada K, Strahler J, Andrews P, Matthews R . Regulation of human methylenetetrahydrofolate reductase by phosphorylation. Proc Natl Acad Sci U S A. 2005; 102(30):10454-9. PMC: 1180802. DOI: 10.1073/pnas.0504786102. View

. Folate-responsive homocystinuria and "schizophrenia'. Nutr Rev. 1982; 40(8):242-5. DOI: 10.1111/j.1753-4887.1982.tb05325.x. View

Narayanan S, McConnell J, Little J, Sharp L, Piyathilake C, Powers H . Associations between two common variants C677T and A1298C in the methylenetetrahydrofolate reductase gene and measures of folate metabolism and DNA stability (strand breaks, misincorporated uracil, and DNA methylation status) in human lymphocytes in.... Cancer Epidemiol Biomarkers Prev. 2004; 13(9):1436-43. View

Almeida O, Flicker L, Lautenschlager N, Leedman P, Vasikaran S, Bockxmeer F . Contribution of the MTHFR gene to the causal pathway for depression, anxiety and cognitive impairment in later life. Neurobiol Aging. 2004; 26(2):251-7. DOI: 10.1016/j.neurobiolaging.2004.03.007. View

10.

Schiepers O, van Boxtel M, De Groot R, Jolles J, Bekers O, Kok F . Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults. Prog Neuropsychopharmacol Biol Psychiatry. 2011; 35(7):1682-8. DOI: 10.1016/j.pnpbp.2011.06.008. View

11.

An X, Lu C, Ma Q, Zhang X, Burgunder J, Lin Q . Association of MTHFR C677T polymorphism with susceptibility to migraine in the Chinese population. Neurosci Lett. 2013; 549:78-81. DOI: 10.1016/j.neulet.2013.06.028. View

12.

Guo T, Chen H, Liu B, Ji W, Yang C . Methylenetetrahydrofolate reductase polymorphisms C677T and risk of autism in the Chinese Han population. Genet Test Mol Biomarkers. 2012; 16(8):968-73. DOI: 10.1089/gtmb.2012.0091. View

13.

Burghardt K, Pilsner J, Bly M, Ellingrod V . DNA methylation in schizophrenia subjects: gender and MTHFR 677C/T genotype differences. Epigenomics. 2012; 4(3):261-8. PMC: 3392683. DOI: 10.2217/epi.12.25. View

14.

Cheng H, Deng Z, Wang Z, Zhang W, Su J . MTHFR C677T polymorphisms are associated with aberrant methylation of the IGF-2 gene in transitional cell carcinoma of the bladder. J Biomed Res. 2013; 26(2):77-83. PMC: 3597322. DOI: 10.1016/S1674-8301(12)60015-3. View

15.

Bousman C, Potiriadis M, Everall I, Gunn J . Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees. Am J Med Genet B Neuropsychiatr Genet. 2013; 165B(1):68-76. DOI: 10.1002/ajmg.b.32209. View

16.

Trimmer E . Methylenetetrahydrofolate reductase: biochemical characterization and medical significance. Curr Pharm Des. 2012; 19(14):2574-93. DOI: 10.2174/1381612811319140008. View

17.

Pejchal R, Campbell E, Guenther B, Lennon B, Matthews R, Ludwig M . Structural perturbations in the Ala --> Val polymorphism of methylenetetrahydrofolate reductase: how binding of folates may protect against inactivation. Biochemistry. 2006; 45(15):4808-18. PMC: 1868400. DOI: 10.1021/bi052294c. View

18.

Lewis S, Zammit S, Gunnell D, Davey Smith G . A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. Am J Med Genet B Neuropsychiatr Genet. 2005; 135B(1):2-4. DOI: 10.1002/ajmg.b.30170. View

19.

Engbersen A, Franken D, Boers G, STEVENS E, Trijbels F, Blom H . Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet. 1995; 56(1):142-50. PMC: 1801334. View

20.

Kelly C, McDonnell A, Johnston T, Mulholland C, Cooper S, McMaster D . The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004; 18(4):567-71. DOI: 10.1177/0269881104047285. View