Methylenetetrahydrofolate reductase variant and schizophrenia/depression

Arinami, Tadao; Yamada, Naoki; Yamakawa‐Kobayashi, Kimiko; Hamaguchi, Hideo; Toru, Michio

doi:10.1002/(sici)1096-8628(19970919)74:5<526::aid-ajmg14>3.0.co;2-e

Cited by 134 publications

(108 citation statements)

References 14 publications

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“…[16][17][18][19][20][21][22][23] The largest of these studies found an OR of 1.63 (1.05-2.53) for risk among TT versus CC homozygotes after adjustment for age and sex, 21 findings which were supported by two further small studies. A random effects meta-analysis of TT versus CC homozygotes gave an OR of 1.37 (1.03-1.82, P = 0.03) for these eight studies.…”

Section: Resultsmentioning

confidence: 81%

“…[16][17][18][19][20][21][22][23] We have looked at the association between the MTHFR C677T polymorphism and three indicators of depression in the British Women's Heart and Health study, a population-based sample of 3487 women. Further, we have carried out a systematic review of all studies to date that have examined the association between MTHFR C677T and indicators of depression and have combined our results from the British Women's Heart and Health Study with those from other studies in a metaanalysis, to provide an overall estimate of the association.…”

Section: Introductionmentioning

confidence: 99%

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The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

et al. 2006

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Low dietary folate intake has been implicated as a risk factor for depression. However, observational epidemiological studies are plagued by problems of confounding, reverse causality and measurement error. A common polymorphism (C677T) in MTHFR is associated with methyltetrahydrofolate reductase (MTHFR) activity and circulating folate and homocysteine levels and offers insights into whether the association between low folate and depression is causal. We genotyped this polymorphism in 3478 women in the British Women's Heart and Health Study. In these women, we looked at the association between genotype and three indicators of depression; ever diagnosed as depressed, currently taking antidepressants and the EuroQol mood question. We also carried out a systematic review and meta-analysis of all published studies which have looked at the association between MTHFR C677T genotype and depression. In the British Women's Heart and Health Study, we found evidence of an increased risk of ever being diagnosed as depressed in MTHFR C677T TT individuals compared with CC individuals, odds ratio (OR) 1.35(95% CI: 1.01, 1.80). Furthermore, we identified eight other studies, which have examined the association between depression and MTHFR C677T. We were able to include all of these studies in our meta-analysis together with our results, obtaining an overall summary OR of 1.36 (95% CI: 1.11, 1.67, P = 0.003). Since this genotype influences the functioning of the folate metabolic pathway, these findings suggest that folate or its derivatives may be causally related to risk of depression.

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Section: Resultsmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

et al. 2006

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“…A total of nine published articles 22,31,33,[36][37][38][39][40][41] reported on the relationship between schizophrenia and the MTHFR 677C4T polymorphism. One article provided data on two separate studies.…”

Section: Mthfr and Schizophreniamentioning

confidence: 99%

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis

Muntjewerff¹,

et al. 2005

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Elevated plasma homocysteine concentration has been suggested as a risk factor for schizophrenia, but the results of epidemiological studies have been inconsistent. The most extensively studied genetic variant in the homocysteine metabolism is the 677C4T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, resulting in reduced enzyme activity and, subsequently, in elevated homocysteine. A meta-analysis of eight retrospective studies (812 cases and 2113 control subjects) was carried out to examine the association between homocysteine and schizophrenia. In addition, a meta-analysis of 10 studies (2265 cases and 2721 control subjects) on the homozygous (TT) genotype of the MTHFR 677C4T polymorphism was carried out to assess if this association is causal. A 5 lmol/l higher homocysteine level was associated with a 70% (95% confidence interval, CI: 27-129) higher risk of schizophrenia. The TT genotype was associated with a 36% (95% CI: 7-72) higher risk of schizophrenia compared to the CC genotype. The performed meta-analyses showed no evidence of publication bias or excessive influence attributable to any given study. In conclusion, our study provides evidence for an association of homocysteine with schizophrenia. The elevated risk of schizophrenia associated with the homozygous genotype of the MTHFR 677C4T polymorphism provides support for causality between a disturbed homocysteine metabolism and risk of schizophrenia.

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“…The sample size in the present study was comparable for schizophrenia, or larger for affective disorders, than that in Arinami et al 1 (297 schizophrenics, 32 patients with major depression, 40 with bipolar disorder, and 419 controls). Although we obtained weak evidence of an increased frequency of homozygosity for the T677 allele in patients with bipolar disorder (P = 0.09 in the total subjects; P = 0.03 in subjects aged less than 45 years), Arinami et al, 1 by contrast, did not find any significant difference in the frequency of homozygosity for the T677 allele between bipolar patients and controls, indicating that our results of moderately increased frequency of homozygosity for the T677 allele in the bipolar group is likely to be attributable to chance. When homozygosity for the T677 allele was considered to be a risk exposure, the present sample size had a power of 90% to detect an odds ratio of 2.0 for schizophrenics, 2.4 for bipolar, and 2.9 for unipolar patients where the critical P-value was set at 0.05.…”

mentioning

confidence: 98%

C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses

et al. 1998

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A common missense mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (C677T) has been shown to be a risk factor for premature cardiovascular disease and neural tube defect. Deficient activity of MTHFR has also been implicated in the pathogenesis of psychiatric conditions such as schizophrenia and affective disorders. Arinami et al 1 found an increased frequency of homozygosity for the mutated type (T677) of the MTHFR gene in schizophrenia and depression. We tried to replicate this finding in a sample of 343 patients with schizophrenia, 143 with bipolar disorder, 71 with unipolar depression, and 258 controls; however, there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.Methylenetetrahydrofolate reductase (MTHFR; EC 1.5.1.20) catalyses the NADPH-linked reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cofactor for methylation of homocysteine to methionine and a compound which possibly serves as the methylation of biogenic amines. Frosst et al 2 identified a common mutation (C677T), which converts an alanine to a valine residue. This mutation is associated with MTHFR activity and plasma homocysteine levels; homocysteine levels in individuals homozygous for the mutated type were almost twice the value for heterozygous or homozygous for the wild-type. Furthermore, the mutation has been shown to be a risk factor for premature cardiovascular disease 3,4 and neural tube defect. 5,6 Deficient activity of MTHFR may also be associated with psychiatric conditions such as mental retardation, schizophrenia, 7-9 and affective disorders. 10 In line with this, a recent study of Arinami et al 1 examined the C677T polymorphism for patients with schizophrenia, bipolar disorder, and depression, and found an increased frequency of homozygosity for the T677 allele among schizophrenics (odds ratio 1.9, P = 0.0006) and among patients with unipolar depression (odds ratio 2.8, P = 0.005), but not among patients with bipolar disorder (odds ratio 1.0). In the present study, we tried to replicate these findings. Table 1 shows the genotype distribution and allele frequency for the C677T polymorphism of the MTHFR gene among the patients with schizophrenia, bipolar disorder, unipolar depression, and controls. The genotype distributions were in Hardy-Weinberg equilibrium for the four groups ( 2 = 0.1, df = 1, ns for the schizophrenics; 2 = 0.6, df = 1, ns for the patients with bipolar disorder; 2 = 0.7, df = 1, ns for the patients with unipolar depression; 2 = 0.9, df = 1, ns for the controls). The frequency of the T677 allele in our control subjects was 0.38, which was consistent with two other Japanese studies; Nshio et al 11 investigated 129 men aged 40-59 years and obtained an allele frequency of 0.38 and Arinami et al 1 reported 0.37 ...

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Methylenetetrahydrofolate reductase variant and schizophrenia/depression

Cited by 134 publications

References 14 publications

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

Homocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis

C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses

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