C677T Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism in Schizophrenia and Bipolar Disorder: An Association Study in Iranian Population
-
Seyed Masoud Arzaghi
,
Arash Hossein-Nezhad
,
Seyed Vahid Shariat
,
Alireza Ghodsipour
,
Jamal Shams
,
Bagher Larijani
Abstract
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.
Method: 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.
Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990; 336: 392-395.
Catoni GL. S-Adenosylmethionine; a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate. J Biol Chem 1953; 204: 403-416.
Anguelova M, Benkelfat C, Turecki G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry 2003; 8: 646-653.
Mohammadi MR, Davidian H, Noorbala AA, Malekafzali H, Naghavi HR, Pouretemad HR, et al. An epidemiological survey of psychiatric disorders in Iran. Clin Pract Epidemiol Ment Health 2005; 1: 16.
Mamdani F, Jaitovich Groisman I, Alda M, Turecki G. Long-term responsiveness to lithium as a pharmacogenetic outcome variable: treatment and etiologic implications. Curr Psychiatry Rep 2003; 5: 484-492.
Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, et al. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56: 162-168.
Michelon L, Vallada H. [Genetics of bipolar disorder]. Rev Bras Psiquiatr 2004; 26 Suppl 3: 12-16.
Craddock N, Dave S, Greening J. Association studies of bipolar disorder. Bipolar Disord 2001; 3: 284-298.
Craddock N, Owen M. Chromosomal aberrations and bipolar affective disorder. Br J Psychiatry 1994; 164: 507-512.
Muntjewerff JW, Kahn RS, Blom HJ, den Heijer M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry 2006; 11: 143-149.
Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660-669.
Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405-411.
Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34-48.
Kirov G, O'Donovan MC, Owen MJ. Finding schizophrenia genes. J Clin Invest 2005; 115: 1440-1448.
Maier W, Hofgen B, Zobel A, Rietschel M. Genetic models of schizophrenia and bipolar disorder: overlapping inheritance or discrete genotypes? Eur Arch Psychiatry Clin Neurosci 2005; 255: 159-166.
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7: 195-200.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10: 111-113.
van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 1998; 62: 1044-1051.
Lievers KJ, Boers GH, Verhoef P, den Heijer M, Kluijtmans LA, van der Put NM, et al. A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med 2001; 79: 522-528.
Rozen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis 1996; 19: 589-594.
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.
Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 1991; 48: 536-545.
Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58: 35-41.
van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995; 346: 1070-1071.
van der Put NM, Eskes TK, Blom HJ. Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM 1997; 90: 111-115.
Lee ES, Chen H, Soliman KF, Charlton CG. Effects of homocysteine on the dopaminergic system and behavior in rodents. Neurotoxicology 2005; 26: 361-371.
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.
Andreoli VM, Maffei F. Letter: Blood-levels of S-adenosylmethionine in schizophrenia. Lancet 1975; 2: 922.
Olney JW. Role of excitotoxins in developmental neuropathology. APMIS Suppl 1993; 40: 103-112.
Muntjewerff JW, van der Put N, Eskes T, Ellenbroek B, Steegers E, Blom H, et al. 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.
Tan EC, Chong SA, Lim LC, Chan AO, Teo YY, Tan CH, et al. Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders. Psychiatr Genet 2004; 14: 227-231.
Joober R, Benkelfat C, Lal S, Bloom D, Labelle A, Lalonde P, et al. Association between the methylenetetrahydrofolate reductase 677C-->T missense mutation and schizophrenia. Mol Psychiatry 2000; 5: 323-326.
Sazci A, Ergul E, Guzelhan Y, Kaya G, Kara I. Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Brain Res Mol Brain Res 2003; 117: 104-107.
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.
Virgos C, Martorell L, Simo JM, Valero J, Figuera L, Joven J, et al. Plasma homocysteine and the methylenetetrahydrofolate reductase C677T gene variant: lack of association with schizophrenia. Neuroreport 1999; 10: 2035-2038.
Muntjewerff JW, Hoogendoorn ML, Kahn RS, Sinke RJ, Den Heijer M, Kluijtmans LA, et al. 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.
Yu L, Li T, Robertson Z, Dean J, Gu NF, Feng GY, et al. No association between polymorphisms of methylenetetrahydrofolate reductase gene and schizophrenia in both Chinese and Scottish populations. Mol Psychiatry 2004; 9: 1063-1065.
Kunugi H, Fukuda R, Hattori M, Kato T, Tatsumi M, Sakai T, et al. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry 1998; 3: 435-437.
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.
Kempisty B, Mostowska A, Gorska I, Luczak M, Czerski P, Szczepankiewicz A, et al. Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett 2006; 400: 267-271.
Lee YS, Han DH, Jeon CM, Lyoo IK, Na C, Chae SL, et al. Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients. Neuroreport 2006; 17: 743-746.
Philibert R, Gunter T, Hollenbeck N, Adams WJ, Bohle P, Packer H, et al. No association of the C677T methylenetetrahydrofolate reductase polymorphism with schizophrenia. Psychiatr Genet 2006; 16: 221-223.
Vilella E, Virgos C, Murphy M, Martorell L, Valero J, Simo JM, et al. Further evidence that hyperhomocysteinemia and methylenetetrahydrofolate reductase C677T and A1289C polymorphisms are not risk factors for schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1169-1174.
Jonsson EG, Larsson K, Vares M, Hansen T, Wang AG, Djurovic S, et al. Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: an association study. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 976-982.
Chen Z, Liu Y, Zhang D, Liu Z, Wang P, Zhou D, et al. C677T methylenetetrahydrofolate reductase gene polymorphisms in bipolar disorder: an association study in the Chinese population and a meta-analysis of genetic association studies. Neurosci Lett 2009; 449: 48-51.
Reif A, Pfuhlmann B, Lesch KP. Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29: 1162-1168.
Ozbek Z, Kucukali CI, Ozkok E, Orhan N, Aydin M, Kilic G, et al. Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1331-1337.
Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation 1998; 98: 2520-2526.
Friso S, Choi SW, Girelli D, Mason JB, Dolnikowski GG, Bagley PJ, et al. A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proc Natl Acad Sci U S A 2002; 99: 5606-5611.
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 1994; 7: 551.
Goyette P, Christensen B, Rosenblatt DS, Rozen R. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet 1996; 59: 1268-1275.
Goyette P, Frosst P, Rosenblatt DS, Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet 1995; 56: 1052-1059.
Lucock M. Folic acid: nutritional biochemistry, molecular biology, and role in disease processes. Mol Genet Metab 2000; 71: 121-138.
Kempisty B, Sikora J, Lianeri M, Szczepankiewicz A, Czerski P, Hauser J, et al. MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatr Genet 2007; 17: 177-181.
Abdolmaleky HM, Thiagalingam S, Wilcox M. Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. Am J Pharmacogenomics 2005; 5: 149-160.
van Vliet J, Oates NA, Whitelaw E. Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 2007; 64: 1531-1538.
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.
Singh SM, McDonald P, Murphy B, O'Reilly R. Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development. Clin Genet 2004; 65: 435-440.
Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Genet 2004; 20: 350-358.
Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 2007; 165: 1-13.
Zintzaras E. C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies. Psychiatr Genet 2006; 16: 105-115.
| Files | ||
| Issue | Vol 6 No 1 (2011) | |
| Section | Articles | |
| Keywords | ||
| Bipolar disorder Methylenetetrahydrofolate reductase Polymorphism Schizophrenia | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
