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

Schizophrenia Research

Volumn 124, Issue 1-3, 2010, Pages 216-222

  Yoshimi, Akira ^a,b   Aleksic, Branko ^a,c   Kawamura, Yukiko ^a,b   Takahashi, Nagahide ^a,d   Yamada, Shinnosuke ^a,b   Usui, Hinako ^a   Saito, Shinichi ^a,e   Ito, Yoshihito ^a   Iwata, Nakao ^c,f   Inada, Toshiya ^g   Noda, Yukihiro ^a,b   Yamada, Kiyofumi ^a   Ozaki, Norio ^a,c  

^a NAGOYA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b MEIJO UNIVERSITY   (Japan)

^c JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

^d MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^e Department of Psychiatry   (Japan)

^f FUJITA HEALTH UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^g SEIWA HOSPITAL   (Japan)

Author keywords

Gene wide association; Japanese population; Meta analysis; Methylenetetrahydrofolate reductase; Schizophrenia

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2);

ARTICLE; CHROMOSOME ANALYSIS; CONTROLLED STUDY; GENE FREQUENCY; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC VARIABILITY; GENOTYPE; HAPLOTYPE; HUMAN; JAPANESE; MAJOR CLINICAL STUDY; MUTATIONAL ANALYSIS; NUCLEOTIDE SEQUENCE; POPULATION GENETICS; PRIORITY JOURNAL; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM;

ADULT; ASIAN CONTINENTAL ANCESTRY GROUP; FEMALE; GENE FREQUENCY; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HAPLOTYPES; HUMANS; MALE; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MIDDLE AGED; POLYMERASE CHAIN REACTION; POLYMORPHISM, SINGLE NUCLEOTIDE; RISK FACTORS; SCHIZOPHRENIA;

EID: 78249274507     PISSN: 09209964     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.schres.2010.07.011     Document Type: Article

References (70)

1. Ades A.E., Lu G., Higgins J.P. The interpretation of random-effects meta-analysis in decision models. Med. Decis. Making 2005, 25(6):646-654.
2. Adzhubei I.A., Schmidt S., Peshkin L., Ramensky V.E., Gerasimova A., Bork P., Kondrashov A.S., Sunyaev S.R. A method and server for predicting damaging missense mutations. Nat. Methods 2010, 7(4):248-249.
3. Allen N.C., Bagade S., McQueen M.B., Ioannidis J.P., Kavvoura F.K., Khoury M.J., Tanzi R.E., Bertram L. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat. Genet. 2008, 40(7):827-834.
4. Andreoli V.M., Maffei F. Letter: blood-levels of S-adenosylmethionine in schizophrenia. Lancet 1975, 2(7941):922.
5. 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(7):646-653.
6. Arinami T., Yamada N., Yamakawa-Kobayashi K., Hamaguchi H., Toru M. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am. J. Med. Genet. 1997, 74(5):526-528.
7. Bakker R.C., Brandjes D.P. Hyperhomocysteinaemia and associated disease. Pharm. World Sci. 1997, 19(3):126-132.
8. Betcheva E.T., Mushiroda T., Takahashi A., Kubo M., Karachanak S.K., Zaharieva I.T., Vazharova R.V., Dimova I.I., Milanova V.K., Tolev T., Kirov G., Owen M.J., O'Donovan M.C., Kamatani N., Nakamura Y., Toncheva D.I. Case-control association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for schizophrenia in the Bulgarian population. J. Hum. Genet. 2009, 54(2):98-107.
9. Blom H.J., Shaw G.M., den Heijer M., Finnell R.H. Neural tube defects and folate: case far from closed. Nat. Rev. Neurosci. 2006, 7(9):724-731.
10. Braff D.L., Freedman R., Schork N.J., Gottesman I.I. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr. Bull. 2007, 33(1):21-32.
11. Burmeister M., McInnis M.G., Zollner S. Psychiatric genetics: progress amid controversy. Nat. Rev. Genet. 2008, 9(7):527-540.
12. Cardon L.R., Palmer L.J. Population stratification and spurious allelic association. Lancet 2003, 361(9357):598-604.
13. Chakravarti A. Population genetics-making sense out of sequence. Nat. Genet. 1999, 21(1 Suppl):56-60.
14. Chen J., Lipska B.K., Halim N., Ma Q.D., Matsumoto M., Melhem S., Kolachana B.S., Hyde T.M., Herman M.M., Apud J., Egan M.F., Kleinman J.E., Weinberger D.R. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet. 2004, 75(5):807-821.
15. Coppen A., Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J. Psychopharmacol. 2005, 19(1):59-65.
16. Craddock N., O'Donovan M.C., Owen M.J. Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr. Bull. 2006, 32(1):9-16.
17. de Bakker P.I., Yelensky R., Pe'er I., Gabriel S.B., Daly M.J., Altshuler D. Efficiency and power in genetic association studies. Nat. Genet. 2005, 37(11):1217-1223.
18. DerSimonian R., Laird N. Meta-analysis in clinical trials. Control. Clin. Trials 1986, 7(3):177-188.
19. Feng L.G., Song Z.W., Xin F., Hu J. Association of plasma homocysteine and methylenetetrahydrofolate reductase C677T gene variant with schizophrenia: a Chinese Han population-based case-control study. Psychiatry Res. 2009, 168(3):205-208.
20. Fleiss J.L., Gross A.J. Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: a critique. J. Clin. Epidemiol. 1991, 44(2):127-139.
21. Freedman R. Schizophrenia. N Engl J. Med. 2003, 349(18):1738-1749.
22. Freeman J.M., Finkelstein J.D., Mudd S.H. Folate-responsive homocystinuria and "schizophrenia". A defect in methylation due to deficient 5, 10-methylenetetrahydrofolate reductase activity. N Engl J. Med. 1975, 292(10):491-496.
23. Garcia-Miss M.D., Perez-Mutul J., Lopez-Canul B., Solis-Rodriguez F., Puga-Machado L., Oxte-Cabrera A., Gurubel-Maldonado J., Arankowsky-Sandoval G. Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677T polymorphism, are risk factors for schizophrenia. J. Psychiatr. Res. 2010, 44(7):441-446.
24. Gilbody S., Lewis S., Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am. J. Epidemiol. 2007, 165(1):1-13.
25. Godfrey P.S., Toone B.K., Carney M.W., Flynn T.G., Bottiglieri T., Laundy M., Chanarin I., Reynolds E.H. Enhancement of recovery from psychiatric illness by methylfolate. Lancet 1990, 336(8712):392-395.
26. Gottesman I.I., Gould T.D. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 2003, 160(4):636-645.
27. Goyette P., Sumner J.S., Milos R., Duncan A.M., Rosenblatt D.S., Matthews R.G., Rozen R. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat. Genet. 1994, 7(2):195-200.
28. Harrison P.J., Weinberger D.R. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol. Psychiatry 2005, 10(1):40-68.
29. Hobbs C.A., Sherman S.L., Yi P., Hopkins S.E., Torfs C.P., Hine R.J., Pogribna M., Rozen R., James S.J. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am. J. Hum. Genet. 2000, 67(3):623-630.
30. Hustad S., Ueland P.M., Vollset S.E., Zhang Y., Bjorke-Monsen A.L., Schneede J. Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clin. Chem. 2000, 46(8 Pt 1):1065-1071.
31. Jonsson E.G., Larsson K., Vares M., Hansen T., Wang A.G., Djurovic S., Ronningen K.S., Andreassen O.A., Agartz I., Werge T., Terenius L., Hall H. Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: an association study. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008, 147B(6):976-982.
32. Joober R., Benkelfat C., Lal S., Bloom D., Labelle A., Lalonde P., Turecki G., Rozen R., Rouleau G.A. Association between the methylenetetrahydrofolate reductase 677C→T missense mutation and schizophrenia. Mol. Psychiatry 2000, 5(3):323-326.
33. Kempisty B., Mostowska A., Gorska I., Luczak M., Czerski P., Szczepankiewicz A., Hauser J., Jagodzinski P.P. Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci. Lett. 2006, 400(3):267-271.
34. Kempisty B., Bober A., Luczak M., Czerski P., Szczepankiewicz A., Hauser J., Jagodzinski P.P. Distribution of 1298A>C polymorphism of methylenetetrahydrofolate reductase gene in patients with bipolar disorder and schizophrenia. Eur. Psychiatry 2007, 22(1):39-43.
35. Kirov G., O'Donovan M.C., Owen M.J. Finding schizophrenia genes. J. Clin. Invest. 2005, 115(6):1440-1448.
36. Kluijtmans L.A., van den Heuvel L.P., Boers G.H., Frosst P., Stevens E.M., van Oost B.A., den Heijer M., Trijbels F.J., Rozen R., Blom H.J. 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(1):35-41.
37. 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(5):435-437.
38. Lee Y.S., Han D.H., Jeon C.M., Lyoo I.K., Na C., Chae S.L., Cho S.C. Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients. NeuroReport 2006, 17(7):743-746.
39. Levine J., Sela B.A., Osher Y., Belmaker R.H. High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog. Neuropsychopharmacol. Biol. Psychiatry 2005, 29(7):1181-1191.
40. Lewis S.J., Lawlor D.A., Davey Smith G., Araya R., Timpson N., Day I.N., Ebrahim S. The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis. Mol. Psychiatry 2006, 11(4):352-360.
41. Marchini J., Howie B., Myers S., McVean G., Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 2007, 39(7):906-913.
42. 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(6):1459-1460.
43. McGuffin P., Knight J., Breen G., Brewster S., Boyd P.R., Craddock N., Gill M., Korszun A., Maier W., Middleton L., Mors O., Owen M.J., Perry J., Preisig M., Reich T., Rice J., Rietschel M., Jones L., Sham P., Farmer A.E. Whole genome linkage scan of recurrent depressive disorder from the depression network study. Hum. Mol. Genet. 2005, 14(22):3337-3345.
44. Munafo M.R., Flint J. Meta-analysis of genetic association studies. Trends Genet. 2004, 20(9):439-444.
45. Muntjewerff J.W., Hoogendoorn M.L., Kahn R.S., Sinke R.J., Den Heijer M., Kluijtmans L.A., Blom H.J. 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(1):69-72.
46. Muntjewerff J.W., Kahn R.S., Blom H.J., den Heijer M. Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol. Psychiatry 2006, 11(2):143-149.
47. O'Donovan M.C., Craddock N., Norton N., Williams H., Peirce T., Moskvina V., Nikolov I., Hamshere M., Carroll L., Georgieva L., Dwyer S., Holmans P., Marchini J.L., Spencer C.C., Howie B., Leung H.T., Hartmann A.M., Moller H.J., Morris D.W., Shi Y., Feng G., Hoffmann P., Propping P., Vasilescu C., Maier W., Rietschel M., Zammit S., Schumacher J., Quinn E.M., Schulze T.G., Williams N.M., Giegling I., Iwata N., Ikeda M., Darvasi A., Shifman S., He L., Duan J., Sanders A.R., Levinson D.F., Gejman P.V., Gejman P.V., Sanders A.R., Duan J., Levinson D.F., Buccola N.G., Mowry B.J., Freedman R., Amin F., Black D.W., Silverman J.M., Byerley W.F., Cloninger C.R., Cichon S., Nothen M.M., Gill M., Corvin A., Rujescu D., Kirov G., Owen M.J. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat. Genet. 2008, 40(9):1053-1055.
48. Pei Y.F., Li J., Zhang L., Papasian C.J., Deng H.W. Analyses and comparison of accuracy of different genotype imputation methods. PLoS ONE 2008, 3(10):e3551.
49. Philibert R., Gunter T., Hollenbeck N., Adams W.J., Bohle P., Packer H., Sandhu H. No association of the C677T methylenetetrahydrofolate reductase polymorphism with schizophrenia. Psychiatr. Genet. 2006, 16(5):221-223.
50. Purcell S., Cherny S.S., Sham P.C. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 2003, 19(1):149-150.
51. Purcell S., Neale B., Todd-Brown K., Thomas L., Ferreira M.A., Bender D., Maller J., Sklar P., de Bakker P.I., Daly M.J., Sham P.C. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 2007, 81(3):559-575.
52. Qian X., Lu Z., Tan M., Liu H., Lu D. A meta-analysis of association between C677T polymorphism in the methylenetetrahydrofolate reductase gene and hypertension. Eur. J. Hum. Genet. 2007, 15(12):1239-1245.
53. Refsum H., Smith A.D., Ueland P.M., Nexo E., Clarke R., McPartlin J., Johnston C., Engbaek F., Schneede J., McPartlin C., Scott J.M. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin. Chem. 2004, 50(1):3-32.
54. Regland B. Schizophrenia and single-carbon metabolism. Prog. Neuropsychopharmacol. Biol. Psychiatry 2005, 29(7):1124-1132.
55. Rioux J.D., Xavier R.J., Taylor K.D., Silverberg M.S., Goyette P., Huett A., Green T., Kuballa P., Barmada M.M., Datta L.W., Shugart Y.Y., Griffiths A.M., Targan S.R., Ippoliti A.F., Bernard E.J., Mei L., Nicolae D.L., Regueiro M., Schumm L.P., Steinhart A.H., Rotter J.I., Duerr R.H., Cho J.H., Daly M.J., Brant S.R. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 2007, 39(5):596-604.
56. 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(1):104-107.
57. 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(7):1113-1123.
58. Schwab S.G., Knapp M., Mondabon S., Hallmayer J., Borrmann-Hassenbach M., Albus M., Lerer B., Rietschel M., Trixler M., Maier W., Wildenauer D.B. Support for association of schizophrenia with genetic variation in the 6p22.3 gene, dysbindin, in sib-pair families with linkage and in an additional sample of triad families. Am. J. Hum. Genet. 2003, 72(1):185-190.
59. Scott J.M., Weir D.G. Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry. J. Cardiovasc. Risk 1998, 5(4):223-227.
60. Shifman S., Bronstein M., Sternfeld M., Pisante-Shalom A., Lev-Lehman E., Weizman A., Reznik I., Spivak B., Grisaru N., Karp L., Schiffer R., Kotler M., Strous R.D., Swartz-Vanetik M., Knobler H.Y., Shinar E., Beckmann J.S., Yakir B., Risch N., Zak N.B., Darvasi A. A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet. 2002, 71(6):1296-1302.
61. Sullivan P.F., Kendler K.S., Neale M.C. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch. Gen. Psychiatry 2003, 60(12):1187-1192.
62. Tan E.C., Chong S.A., Lim L.C., Chan A.O., Teo Y.Y., Tan C.H., Mahendran R. Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders. Psychiatr. Genet. 2004, 14(4):227-231.
63. The Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3000 shared controls. Nature 2007, 447(7145):661-678.
64. van der Put N.M., Steegers-Theunissen R.P., Frosst P., Trijbels F.J., Eskes T.K., van den Heuvel L.P., Mariman E.C., den Heyer M., Rozen R., Blom H.J. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995, 346(8982):1070-1071.
65. van der Put N.M., Gabreels F., Stevens E.M., Smeitink J.A., Trijbels F.J., Eskes T.K., van den Heuvel L.P., Blom H.J. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. Am. J. Hum. Genet. 1998, 62(5):1044-1051.
66. Vilella E., Virgos C., Murphy M., Martorell L., Valero J., Simo J.M., Joven J., Fernandez-Ballart J., Labad A. Further evidence that hyperhomocysteinemia and methylenetetrahydrofolate reductase C677T and A1289C polymorphisms are not risk factors for schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2005, 29(7):1169-1174.
67. Virgos C., Martorell L., Simo J.M., 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(10):2035-2038.
68. Yu L., Li T., Robertson Z., Dean J., Gu N.F., Feng G.Y., Yates P., Sinclair M., Crombie C., Collier D.A., 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(12):1063-1065.
69. Zeggini E., Weedon M.N., Lindgren C.M., Frayling T.M., Elliott K.S., Lango H., Timpson N.J., Perry J.R., Rayner N.W., Freathy R.M., Barrett J.C., Shields B., Morris A.P., Ellard S., Groves C.J., Harries L.W., Marchini J.L., Owen K.R., Knight B., Cardon L.R., Walker M., Hitman G.A., Morris A.D., Doney A.S., McCarthy M.I., Hattersley A.T. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007, 316(5829):1336-1341.
70. Zou C.G., Banerjee R. Homocysteine and redox signaling. Antioxid. Redox Signal. 2005, 7(5-6):547-559.