Additive effect of MTHFR and GRIN1 genetic polymorphisms on the risk of schizophrenia

Document Type : Original article

Authors

Department of Genetics, College of Sciences, Shahid Chamran University, Ahvaz 61357-44337, Iran

Abstract

Schizophrenia is a complex disorder with polygenic inheritance. The MTHFR gene (OMIM: 607093) plays an important role in the folate metabolism. It has been suggested that C677T (rs1801133) and A1298C (rs1801131) genetic polymorphisms in the MTHFR gene lead to the decreased activity of the methylenetetrahydrofolate reductase enzyme which may have significant effect on developing schizophrenia. We used a case-control study to establish the possible association between the C677T and the A1298C polymorphisms and susceptibility to schizophrenia in an Iranian population. The genotypes of the polymorphisms were determined using PCR-RFLP. The data were analyzed by logistic regression model. Data analysis revealed that the combination genotypes of 677CT/1298AA, 677CC/1298CC, 677TT/1298AA, 677CT/ 1298AC and 677CT/1298CC increase the risk of schizophrenia. In order to evaluate the effect of combined genotypes of the three mentioned polymorphic loci, the frequencies of the compound genotypes were compared between control and patient groups (Table 4). Base on the results, the existence of >4 risk factors showed about 32-fold increased risk for schizophrenia (OR=32.3, 95% CI: 5.52-188, P=<0.001).

Keywords

References

1. O’Donovan MC, Williams NM, Owen MJ. Recent advances in the genetics of schizophrenia. Hum Mol Genet 2003;12:R125-R133.
2. Muntjewerff JW, Hoogendoorn ML, Kahn RS, Sinke RJ, Den Heijer M, Kluijtmans LA, Blom HJ. Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case–control study. Am J Med Genet B Neuropsychiatr Genet 2005;135B:69-72.
3. Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet 2005;14:47-58.
4. Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbottom D, Conley MR, Weir DG, Scott JM. Thermolabile variant of 5, 10-methylenetetrahydrofolate reductase associated with low red-cell folates; implications for folate intake recommendations. Lancet 1997;349:1591-1593.
5. Nishimura M, Yoshino K, Tomita Y, Takashima S, Tanaka J, Narisawa K, Kurobane I. Central and peripheral nervous system pathology of homocystinuria due to 5, 10-methylenete-trahydrofolate reductase deficiency. Pediatr Neurol 1985;6:375-378.
6. Kohn Y, Danilovich E, Filon D, Oppenheim A, Karni O, Kanyas K, Turetsky N, Korner M, Lerer B. Linkage disequilibrium in the
DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: findings from identity by descent haplotype sharing analysis. Am J Med Genet B Neuropsychiatr Genet 2004;128:65-70.
7. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuve LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10:111-113.
8. Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1999;4:511-512.
9. Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 1996;19:589-594.
10. Lievers KJ, Boers GH, Verhoef P, den Heijer M, Kluijtmans LA, van der Put NM, Trijbels F, Blom HJ. A second common variant in the methylenetetrahydrofolate reductase (
MTHFR) gene and its relationship to MTHFR enzyme activity, homo-cysteine, and cardiovascular disease risk. J Mol Med 2001;79:522-528.
11. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG.
MTHFR 677C> T polymorphism and risk of coronary heart disease: a meta- analysis. JAMA 2002; 288: 2023-2031.
12. Matthews RG. Methylenetetrahydrofolate reductase: a common human polymorphism and its biochemical implications. Chem Rec 2002;2:4-12.
13. Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990;336:392-395.
14. Regland B, Germgard CG, Gottfries CG, Grenfeldt B, Koch-Schmidt AC. Homozygous thermolabile methylenethetrahy-drofolate reductase in schizophrenia-like psychosis. J Neural Transm 1997;104:931-941.
15. Susser E, Brown AS, Klonowski E, Allen RH, Lindenbaum J. Schizophrenia and impaired homocysteine metabolism: a possible association. Biol Psychaitry 1998;44:141-143 
16. Levine J, Sela BA, Osher Y, Belmaker RH. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1181-1191.
17. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1995;340:1449-1454.
18. Arinami T, Yamada N, Yamakawa-Kobayashi K, Hamaguchi H, Toru M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet 1997;74:526-528.
19. Kunugi H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T, Hirose T Nanko S. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry 1998;3:435-437.
20. Virgos C, Martorell L, Simo JM, Valero J, Figuera L, Joven J, Labad A, Vilella E. Plasma homocysteine and the methylenetetrahydrofolate reductase C677T gene variant: lack of association with schizophrenia. Neuroreport 1999;10:2035-2038.
21. Joober R, Benkelfat C, Lal S, Bloom D, Labelle A, Lalonde P, Turecki, G, Rozen R, Rouleau GA. Association between the methylenetetrahydrofolate reductase 677C–T missense mutation and schizophrenia. Mol Psychiatry 2000;5:323-326.
22. Yu L, Li T, Robertson Z, Dean J, Gu NF, Feng GY, Yates P, Sinclair M, Crombie C, Collier DA, Walker N, He L, St Clair D. No association between polymorphisms of methylenetetrahydrofolate reductase gene and schizophrenia in both Chinese and Scottish populations. Mol Psychiatry 2004;9:1063–1065.
23. Vilella E, Virgos C, Murphy M, Martorell L, Valero J, Simo JM, Joven J, Fernandez-Ballart J, Labad A. Further evidence that hyperhomocysteinemia and methylenetetrah-ydrofolate reductase C677T and A1289C polymorphisms are not risk factors for schizophrenia. Prog Neuropsychopharmacol Biol Psych 2005;29:1169-1174.
24. Sazci A, Ergul E, Kucukali I, Kara I, Kaya G. Association of the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene with schizophrenia: association is significant in men but not in women. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:1113-1123.
 25. Kempisty B, Mostowska A, Gorska I, Luczak M, Czerski P, Szczepankiewicz A, Joanna Hauser J, Jagodziński PP. Association of 677C>T polymorphism of methylenetetrahydr-ofolate reductase (
MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett 2006;400: 267-271.
26. Kempisty B, Bober A, quczak M, Czerski P, Szczepankiewicz A, Hauser J, Jagodziński PP. Distribution of 1298A>C polymorphism of methylenetetrahydro-folate reductase gene in patients with bipolar disorder and schizophrenia. Eur Psychiat 2007;22:39-43.
27. Muntjewerff JW, Gellekink H, den Heijer M, Hoogendoorn MLC, René S, Kahn RS, Richard J. Sinke RJ, Henk J. Blom HJ. Polymorphisms in catechol-O-methyltransferase and methylenetetrahydrofolate reductase in relation to the risk of schizophrenia. Eur Neuropsychopharm 2008;18:99-106.
28. Rosenquist TH, Schneider AM, Monaghan DT. N-methyl-D-aspartate receptor agonists modulate homocysteine-induced developmental abnormalities. FASEB J 1999;13:1523-1531.
29. Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev. Neurosci; 1994;17: 31-108.
30. Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, Derrick R. Arnelle DR, Jonathan S, Stamler JS. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-Daspartate receptor. Proc Natl Acad Sci USA 1997; 94:5923-5928.
31. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Nail Burnashev, Bert Sakmann, Peter HS. Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science 1992;256:1217-1221
32. Coyle JT, Tsai GC. NMDA receptor function, neuroplasticity, and the pathophysio-logy of schizophrenia. Disord Synaptic Plast Schizophr 2004;59:491-515.
33. Galehdari H, Pooryasin A, Foroughmand AM, Daneshmand S, Saadat M. Association between the G1001C polymorphism in the
GRIN1 gene and Schizophrenia in the Iranian population. J Mol Neurosci 2009;38:178-181.
34. Kara I, Sazci A, Ergul E, Kaya G, Kilic G. Association of the C677T and A1298C polymorphisms in the 5, 10 methylenetetrahydrofolate reductase gene in patients with migraine risk. Mol Brain Res 2003;111:84-90.
35. Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis Ellison R, Eckfeldt JH, Rozen R. The A1298C polymorphism in methylenetetrahydrofolate reductase (
MTHFR): in vitro expression and association with homocysteine. Atherosclerosis 2001;156:409-415.
36. Muntjewerff JW, van der Put N, Eskes T, Ellenbroek B, Steegers E, Blom H, Zitman F. Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia. Psychiatry Res 2003;121:1-9.
37. Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M. Homocysteine, methylenetetra-hydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry 2006;11:143-149.
38. Van Der Put NM, Gabreels F, Stevens EMB, Smeitink JAM, Trijbels FJM, Eskes TKAB, van den Heuvel LP, Blom HJ. A second common mutation in the methyle-netetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 1998;62:1044-1051.
39. Shi J, Gershon ES, Liu C. Genetic associations with schizophrenia: Meta-analyses of 12 candidate genes. Schizophr Res 2008;104:96-107.
40. Matsushita S, Muramatsu T, Arai H, Matsui T, Higuchi S. The frequency of the methylenetetrahydrofolate reductase-gene mutation varies with age in the normal population, Am J Hum Genet 1997;61:1459-1460.
41. Picker JD, Coyle JT. Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia? Harv Rev Psychiatry 2005;13:197-205.
42. Singh SM, Murphy B, O’Reilly RL. Involvement of gene-diet/drug interaction in DNA methylation and its contribution to complex diseases: from cancer to schizophrenia. Clin Genet 2003;64:451-460.
43. Singh SM, McDonald P, Murphy B. O'Reilly RL. Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development. Clin Genet 2004;65:435-440.
44. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (
MTHFR) genetic polymorphisms and psychiatric disorders: A HuGE review. Am J Epidemiol 2007;165:1-13.
45. Elliott GR, Sutherland K, Erdelyi E, Ciaranello RD, Barchas JD, Wyatt RJ. N-5, 10-methylenetetrahydrofolate reductase activity in autopsied brain parts of chronic schizophrenics and controls and in vitro tryptoline formation. Biol Psychiatry 1978; 13:695-708.
46. Sherer MA, Cantoni MA, Golden RN, Rudorfer MV, Potter WZ. Effects of S-adenosylmethionine on plasma norepinephrine, blood pressure, and heart rate in healthy volunteers. Psychiatry Res 1986;2:111-118.
47. Selhub JL, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transulfuration of homocysteine. Am J Clin Nutr 1991;55:131-138.
48. Applebaum J, Shimon H, Sela BA, Belmaker RH, Levine J. Homocysteine levels in newly admitted schizophrenic patients. J Psychiatr Res 2004;38:413-416.
49. Levine J, Stahl Z, Sela BA, Gavendo S, Ruderman V, Belmaker RH. Elevated homocysteine levels in young male patients with schizophrenia. Am J Psychiatry 2002;159:1790-1792.
50. Osher Y, Sela BA, Levine J, Belmaker RH. Elevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration. Bipolar Disord 2004;1:82-86.
51. Yao JK, Reddy RD, van Kammen DP. Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs 2001;15: 287-310.
52. Dimitrova KR, DeGroot KW, Suyderhoud JP, Pirovic EA, Munro TJ, Wieneke J, Myers AK, Kim YD. 17-B estradiol preserves endothelial cell viability in an in vitro model of homocysteine-induced oxidative stress. J Cardiovasc Pharm 2002; 39:347-353.
53. Catts VS, Catts SV. Apoptosis and schizophrenia: Is the tumour suppressor gene, p53, a candidate susceptibility gene? Schizophr Res 2000;41:405-415.
54. Jarskog LF, Gilmore JH, Selinger ES, Lieberman JA. Cortical bcl-2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiat 2000;48:641-650.
55. Mattson MP, Shea TB. Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders. Trends Neurosci 2003;26:137-146.
56. Kamudhamas A, Pang L, Smith SD, Sadovsky Y, Nelson DM. Homocysteine thiolactone induces apoptosis in cultured human trophoblasts: a mechanism for homocysteine-mediated placental dysfunction? Am J Obstet Gynecol 2004;191: 563-571.

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