Age Matters: an Atypical Association Between Polymorphism of MTHFR and Clinical Phenotypes in Children with Schizophrenia

  • Lin Wan
  • Yuhong Li
  • Yuming Zhou
  • Rena LiEmail author
  • Yi ZhengEmail author


Methylenetetrahydrofolate reductase (MTHFR) polymorphism may increase the risk of schizophrenia in adults and aggravate related symptoms, while it is unknown whether similar risk applies in children with schizophrenia. While average onset age of schizophrenia is between the ages of 15 and 25, there are no studies on the relationship between MTHFR polymorphism and childhood-onset schizophrenia (COS). Here, we aimed to explore the risk of MTHFR polymorphism in children and examine the effects of MTHFR polymorphism on disease onset and clinical features in the COS patients. Pediatric patients with schizophrenia (n = 97) as well as age- and sex-matched controls (n = 92) were enrolled from the pediatric department. We evaluated clinical features including disease onset age, duration, Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), and Clinical Global Impression (CGI). The three major MTHFR genotypes (G1793A, C677T, and A1298C) were examined in all subjects and the association between MTHFR polymorphism and clinical features of schizophrenia was analyzed. The G1793A polymorphism and the total number of MTHFR risk alleles were associated with an increased risk of schizophrenia in children. The A1298C polymorphism contributed to prolong the duration time of schizophrenia. Inconsistent with expectations, no significant associations were found between MTHFR C677T polymorphism and schizophrenia in children. Both G1793A and multi-site MTHFR polymorphisms are associated with an increased risk of schizophrenia in children, while A1298C polymorphism contributes to prolonged disease duration. While C677T is known to play major roles in the risk of adult schizophrenia, our finding for the first time suggests an age-specific association between MTHFR polymorphisms and schizophrenia.


Methylenetetrahydrofolate reductase Polymorphism Schizophrenia Children Clinical symptom Disease duration 



We thank for all patients and healthy subjects for their participation in the study, and Drs. Zuoli Sun, Zhengrong Zhang, Yi He, Christine, and clinical researchers from Beijing Anding Hospital, Capital Medical University for their support and help.

Funding Information

This work was financially supported by the Beijing Municipal Science & Technology Commission under grant (Z161100000216151) and the National Natural Science Foundation of China under grant (81671248).

Compliance with Ethical Standards

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. Applebaum J, Shimon H, Sela BA, Belmaker RH, Levine J (2004) Homocysteine levels in newly admitted schizophrenic patients. J Psychiatr Res 38(4):413–416Google Scholar
  2. Asarnow RF, Forsyth JK (2013) Genetics of childhood-onset schizophrenia. Child Adolesc Psychiatr Clin N Am 22(4):675–687. Google Scholar
  3. Burd LKJ (1987) A North Dakota prevalence study of schizophrenia presenting in childhood. J Am Acad Child Adolesc Psychiatry 26:347–350Google Scholar
  4. Carlsson A, Carlsson ML (2006) A dopaminergic deficit hypothesis of schizophrenia: the path to discovery. Dialogues Clin Neurosci 8(1):137–142Google Scholar
  5. Del Pino I, Rico B, Marin O (2018) Neural circuit dysfunction in mouse models of neurodevelopmental disorders. Curr Opin Neurobiol 48:174–182. Google Scholar
  6. Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35(3):528–548. Google Scholar
  7. Friso S, Choi SW (2005) Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab 6(1):37–46Google Scholar
  8. Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Gueant JL, Landolt MA, Kozich V, Fowler B, Baumgartner MR (2016) Mutation update and review of severe methylenetetrahydrofolate reductase deficiency. Hum Mutat 37(5):427–438. Google Scholar
  9. Goghari VM, Sponheim SR (2008) Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder. Schizophr Res 103(1–3):186–191. Google Scholar
  10. Gonzalez-Castro TB, Hernandez-Diaz Y, Juarez-Rojop IE, Lopez-Narvaez ML, Tovilla-Zarate CA, Fresan A (2016) The role of a catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism in schizophrenia: a systematic review and updated meta-analysis on 32,816 subjects. NeuroMolecular Med 18(2):216–231. Google Scholar
  11. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 7(4):551Google Scholar
  12. Goyette P, Christensen B, Rosenblatt DS, Rozen R (1996) Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet 59(6):1268–1275Google Scholar
  13. Hu CY, Qian ZZ, Gong FF, Lu SS, Feng F, Wu YL, Yang HY, Sun YH (2015) Methylenetetrahydrofolate reductase (MTHFR) polymorphism susceptibility to schizophrenia and bipolar disorder: an updated meta-analysis. J Neural Transm (Vienna, Austria : 1996) 122(2):307–320. Google Scholar
  14. Jönsson EG, Larsson K, Vares M, Hansen T, Wang AG, Djurovic S, Rønningen KS, Andreassen OA, Agartz I, Werge T (2010) Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: an association study. Am J Med Genet Part B Neuropsychiatr Genet 147B(6):976–982Google Scholar
  15. Joseph L, Ziva S, Ben Ami S, Slava G, Vladimir R, Belmaker RH (2002) Elevated homocysteine levels in young male patients with schizophrenia. Am J Psychiatr 159(10):1790–1792Google Scholar
  16. Kempisty B, Mostowska A, Gorska I, Luczak M, Czerski P, Szczepankiewicz A, Hauser J, Jagodzinski PP (2006) Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett 400(3):267–271. Google Scholar
  17. Kim SG, Song JY, Joo EJ, Jeong SH, Kim SH, Lee KY, Lee NY, Ahn YM, Kim YS, Roh MS (2011) No association of functional polymorphisms in methlylenetetrahydrofolate reductase and the risk and minor physical anomalies of schizophrenia in Korean population. J Korean Med Sci 26(10):1356–1363. Google Scholar
  18. Levine J, Stahl Z, Sela BA, Ruderman V, Shumaico O, Babushkin I, Osher Y, Bersudsky Y, Belmaker RH (2006) Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry 60(3):265–269Google Scholar
  19. Lewis SJ, Zammit S, Gunnell D, Smith GD (2005) A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. Am J Med Genet B Neuropsychiatr Genet 135b(1):2–4. Google Scholar
  20. Li WX, Cheng F, Zhang AJ, Dai SX, Li GH, Lv WW, Zhou T, Zhang Q, Zhang H, Zhang T, Liu F, Liu D, Huang JF (2017) Folate deficiency and gene polymorphisms of MTHFR, MTR and MTRR elevate the hyperhomocysteinemia risk. Clin Lab 63(3):523–533. Google Scholar
  21. Liew SC, Gupta ED (2015) Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. Eur J Med Genet 58(1):1–10. Google Scholar
  22. McGrath J, Saha S, Chant D, Welham J (2008) Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30:67–76. Google Scholar
  23. McTeague LM, Huemer J, Carreon DM, Jiang Y, Eickhoff SB, Etkin A (2017) Identification of common neural circuit disruptions in cognitive control across psychiatric disorders. Am J Psychiatry 174(7):676–685. Google Scholar
  24. Melas PA, Rogdaki M, Osby U, Schalling M, Lavebratt C, Ekstrom TJ (2012) Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J 26(6):2712–2718. Google Scholar
  25. Muntjewerff JW, Hoogendoorn ML, Kahn RS, Sinke RJ, Den Heijer M, Kluijtmans LA, Blom HJ (2005) Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study. Am J Med Genet B Neuropsychiatr Genet 135B(1):69–72. Google Scholar
  26. Nanitsos EK, Nguyen KT, St'astny F, Balcar VJ (2005) Glutamatergic hypothesis of schizophrenia: involvement of Na+/K+-dependent glutamate transport. J Biomed Sci 12(6):975–984. Google Scholar
  27. Nishi A, Numata S, Tajima A, Kinoshita M, Kikuchi K, Shimodera S, Tomotake M, Ohi K, Hashimoto R, Imoto I, Takeda M, Ohmori T (2014) Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull 40(5):1154–1163. Google Scholar
  28. O'Tuathaigh CM, Fumagalli F, Desbonnet L, Perez-Branguli F, Moloney G, Loftus S, O'Leary C, Petit E, Cox R, Tighe O, Clarke G, Lai D, Harvey RP, Cryan JF, Mitchell KJ, Dinan TG, Riva MA, Waddington JL (2017) Epistatic and independent effects on schizophrenia-related phenotypes following co-disruption of the risk factors Neuregulin-1 x DISC1. Schizophr Bull 43(1):214–225. Google Scholar
  29. Peerbooms OLJ, Os JV, Drukker M, Kenis G, Hoogveld L, Hert MD, Delespaul P, Winkel RV, Rutten BPF (2011) Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun 25(8):1530–1543Google Scholar
  30. Rai V, Yadav U, Kumar P, Yadav SK, Gupta S (2017) Methylenetetrahydrofolate reductase A1298C genetic variant& risk of schizophrenia: a meta-analysis. Indian J Med Res 145(4):437–447. Google Scholar
  31. Remschmidt HE, Schulz E, Martin M, Warnke A, Trott GE (1994) Childhood-onset schizophrenia: history of the concept and recent studies. Schizophr Bull 20(4):727–745Google Scholar
  32. Renou S, Hergueta T, Flament M, Mouren-Simeoni MC, Lecrubier Y (2004) Diagnostic structured interviews in child and adolescent's psychiatry. Encephale 30(2):122–134Google Scholar
  33. Roffman JL, Weiss AP, Deckersbach T, Freudenreich O, Henderson DC, Purcell S, Wong DH, Halsted CH, Goff DC (2007) Effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism on executive function in schizophrenia. Schizophr Res 92(1–3):181–188. Google Scholar
  34. Roffman JL, Weiss AP, Purcell S, Caffalette CA, Freudenreich O, Henderson DC, Bottiglieri T, Wong DH, Halsted CH, Goff DC (2008) Contribution of methylenetetrahydrofolate reductase (MTHFR) polymorphisms to negative symptoms in schizophrenia. Biol Psychiatry 63(1):42–48. Google Scholar
  35. Saetre P, Vares M, Werge T, Andreassen OA, Arinami T, Ishiguro H, Nanko S, Tan EC, Han DH, Roffman JL, Muntjewerff JW, Jagodzinski PP, Kempisty B, Hauser J, Vilella E, Betcheva E, Nakamura Y, Regland B, Agartz I, Hall H, Terenius L, Jonsson EG (2011) Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and age of onset in schizophrenia: a combined analysis of independent samples. Am J Med Genet B Neuropsychiatr Genet 156(2):215–224. Google Scholar
  36. Taylor EH (1998) Advances in the diagnosis and treatment of children with serious mental illness. Child Welfare 77(3):311–332Google Scholar
  37. van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ (1998) A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62(5):1044–1051. Google Scholar
  38. Yadav U, Kumar P, Gupta S, Rai V (2016) Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: an updated meta-analysis. Asian J Psychiatr 20:41–51. Google Scholar
  39. Yoshimi A, Aleksic B, Kawamura Y, Takahashi N, Yamada S, Usui H, Saito S, Ito Y, Iwata N, Inada T, Noda Y, Yamada K, Ozaki N (2010) Gene-wide association study between the methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population, with an updated meta-analysis on currently available data. Schizophr Res 124(1–3):216–222. Google Scholar
  40. Zhang C, Xie B, Du YS, Cheng WH, Fang YR, Yu SY (2010) Further evidence that methylenetetrahydrofolate reductase A1298C polymorphism is a risk factor for schizophrenia. J Neural Transm 117(9):1115–1117. Google Scholar
  41. Zintzaras E (2006) C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies. Psychiatr Genet 16(3):105–115. Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Beijing Institute of Brain DisordersCapital Medical UniversityBeijingChina
  2. 2.Collaborative Innovation Center for Brain DisordersCapital Medical UniversityBeijingChina
  3. 3.Beijing Key Laboratory of Mental DisordersBeijing Anding HospitalBeijingChina
  4. 4.Roskamp InstituteSarasotaUSA

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