Mthfr and Schizophrenia but No Family History of Schizophrenia
Abstract
Previous studies suggest that elevated blood homocysteine levels and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for schizophrenia. However, the effects of gender and MTHFR C677T genotypes on blood homocysteine levels in schizophrenia take not been consistent. We first investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in controls with stratification by gender and by the MTHFR C677T genotypes in a large cohort (N = 1379). Second, nosotros conducted a meta-analysis of association studies betwixt claret homocysteine levels and schizophrenia separately by gender (N = 4714). Tertiary, we performed a case-command association study between the MTHFR C677T polymorphism and schizophrenia (Due north = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the issue of plasma total homocysteine levels on schizophrenia by a mendelian randomization arroyo. The ANCOVA afterwards adjustment for age demonstrated a pregnant upshot of diagnosis on the plasma total homocysteine levels in all strata, and the subsequent meta-analysis for gender demonstrated elevated blood homocysteine levels in both male and female patients with schizophrenia although antipsychotic medication might influence the consequence. The meta-assay of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization assay in the Japanese populations yielded an OR of i.fifteen for schizophrenia per 1-SD increase in plasma full homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased take chances of schizophrenia.
Introduction
Schizophrenia is a devastating psychiatric disorder with a median lifetime prevalence rate of 0.vii%–0.8%. ane Accumulating show has shown that alterations in 1-carbon metabolism might play an important role in the pathogenesis of schizophrenia. two,3 A number of studies accept been conducted to evaluate the clan between blood homocysteine levels and schizophrenia. The majority of these studies accept demonstrated elevated blood homocysteine levels in patients with schizophrenia compared with controls. iv–24 All the same, several studies have reported no significant diagnostic differences in the blood homocysteine levels between the 2 groups. 25–31
To date, 1 report has examined an association between blood homocysteine levels and schizophrenia by conducting a meta-assay of 8 case-command studies (a total number of 812 cases with schizophrenia and 2113 control subjects) and demonstrated that a 5 μmol/50 increase in homocysteine concentration was associated with a higher risk of schizophrenia (OR = i.seven; 95% CI = 1.27–two.29). 32 However, this meta-assay was performed without consideration of the result of gender. Higher blood homocysteine levels in men than in women have been reported, 33 and the results of the previous association studies between blood homocysteine levels and schizophrenia with stratification by gender are inconclusive. In some studies, elevated blood homocysteine levels were observed in only male patients with schizophrenia and not in female person patients, 5,six,x,19 whereas other studies have demonstrated that both male and female patients with schizophrenia had increased blood homocysteine levels. 11,17
Claret homocysteine levels are as well influenced by genetic variations. 34,35 Amid these variants, i common functional single nucleotide polymorphism (SNP) of the methylenetetrahydrofolate reductase (MTHFR) gene, C677T (rs1801133), has been investigated well. The MTHFR C677T polymorphism results in amino acid substitution (Ala222Val) and causes a reduction of enzyme activeness and college homocysteine levels. 36 The results of the previous association studies betwixt blood homocysteine levels and schizophrenia with stratification by C677T genotypes are inconclusive. A significant diagnostic difference in blood homocysteine levels has been institute only in the subjects carrying the CT genotype or simply in the subjects carrying the TT genotype. seven,eighteen However, Feng et al 16 showed a pregnant diagnostic departure for both CT and TT genotype carriers.
Many genetic example-control clan studies between the MTHFR C677T polymorphism and schizophrenia have been performed in various populations, and the results of these association studies are not consistent. Just i study of the Japanese population reported a significant association between the MTHFR C677T polymorphism and schizophrenia, while the other 3 studies of the Japanese population accept not replicated this positive finding. 37–forty Yet, several meta-analyses of association studies have revealed a meaning clan between this SNP and schizophrenia. 39,41–47
In this study, nosotros get-go investigated whether plasma total homocysteine levels were higher in patients with schizophrenia than in nonpsychiatric controls with stratification by gender and by the MTHFR C677T genotypes in a big cohort (N = 1379). Second, we conducted a meta-analysis of association studies betwixt the blood homocysteine levels and schizophrenia separately past gender to evaluate a precise estimation of the association (Due north = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and carried out a meta-analysis of genetic association studies of this SNP with schizophrenia based on Japanese subjects to determine whether the MTHFR C677T polymorphism was genetically implicated in schizophrenia in the Japanese population (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization (MR) approach, a useful tool for assessing causal associations in observational data. 48,49
Methods
Subjects of the Association Study Between the Plasma Full Homocysteine Levels and Schizophrenia
Three hundred and eighty-one patients with schizophrenia (225 men, mean historic period: 58.two±nine.three y; 156 women, hateful age: 59.4±9.7 y) were recruited from Tokushima University Infirmary in Japan. The diagnosis of schizophrenia was fabricated co-ordinate to Diagnostic and Statistical Transmission of Mental Disorders (DSM)-IV criteria by at least 2 expert psychiatrists on the footing of extensive clinical interviews and a review of medical records. None of the patients had any psychiatric comorbidity or cardiovascular diseases. All patients were treated with various antipsychotic drugs. The mean chlorpromazine equivalent dose was 689.6±581.3mg/d. Nine hundred and ninety-eight control subjects (331 men, mean age: 38.3±12 y; 667 women, mean age: 43.0±11.ix y) were selected from volunteers who were recruited from hospital staff, students, and company employees documented to be gratis from psychiatric issues and past histories of mental illness. All subjects who participated in this study were of Japanese origin. All subjects signed written informed consent approved past the institutional ideals committees of the University of Tokushima Graduate Schoolhouse. Of 1379 subjects used in this association written report, 1357 with genomic DNA (377 patients and 980 controls) were used in the side by side genetic association study.
Subjects of the Association Written report Between the MTHFR C677T Polymorphism and Schizophrenia
Two example-control sets were used: the Tokushima sample set up (A southern island of Japan) and the Osaka sample fix (Midwestern Nippon). Both sets accept been described in previous studies. 50,51 For the Tokushima sample set up, 1149 patients with schizophrenia (676 males, 473 females, mean age: 54.6±14.nine y) were recruited from the Tokushima and Kochi University Hospitals in Nihon. The diagnosis of schizophrenia was fabricated co-ordinate to DSM-Four criteria. A total of 2742 control subjects (1230 males, 1512 females, mean age: 38.8±12.6 y) were selected from volunteers. For the Osaka sample set, 621 patients with schizophrenia (302 males, 319 females, mean age: 46.five±15.8 y) were recruited from Osaka University Hospital in Japan. The diagnosis of schizophrenia was fabricated according to DSM-IV criteria. A total of 486 control subjects (231 males, 255 females, hateful historic period: 35.0±12.7 y) were selected from volunteers. All subjects signed written informed consent approved by the institutional ethics committees of the University of Tokushima Graduate School, Kochi Medical School, and University of Osaka Graduate School.
Plasma Total Homocysteine Analysis
Plasma total homocysteine levels were measured by high-operation liquid chromatography. Homocysteine was labeled with four-fluoro-vii-sulfamoylbenzofurazan and detected by a fluorescent detector according to the method of a previous study. 52
MTHFR Genotyping
We genotyped the MTHFR C677T polymorphism by using a commercially available TaqMan probe with the Applied Biosystems 7500 Fast Real Time PCR Organization, according to the protocol recommended by the manufacturer (Applied Biosystems, California, United states of america). Twelve percent of the genotypes were genotyped again, and there were no mismatches between the 2 genotyping steps.
Study Selection for the Meta-analysis of Association Studies Between Claret Homocysteine Levels and Schizophrenia
Eligible studies were identified using the PubMed search engine with the terms "homocysteine," "hyperhomocysteinemia," and "schizophrenia." Nosotros also conducted an boosted manual search of reference lists and review articles. Studies coming together the following criteria were included for further meta-analysis: (1) included laboratory assessment of serum or plasma homocysteine levels, (ii) performed a example-command report (schizophrenia vs command), (iii) provided raw data of homocysteine levels separately past gender, and (four) published in an English language. The 2 reviewers (Northward.S. and One thousand.K.) selected the articles independently according to the inclusion criteria, and then discussed the articles until they reached a consensus on every report used for the meta-analysis.
Statistical Methods
A linear regression analysis was used to examine the furnishings of diagnosis, historic period, gender, and the MTHFR C677T genotypes on the plasma full homocysteine. An ANCOVA was performed to examine the presence of the differences in the plasma total homocysteine between the 2 groups (schizophrenia vs control) separately by gender and by the 3 MTHFR C677T genotypes (total of half dozen strata). Allelic and genotypic frequencies of the MTHFR C677T polymorphism in patients and control subjects were compared using the χ2 exam. In gild to quantify the strength of association betwixt plasma full homocysteine and schizophrenia, an MR approach was used, as in a previous report. 53 The risk gauge in gene-schizophrenia clan for the TT genotypes of the MTHFR C677T polymorphism (vs the CC genotypes; ORSCZ/TT) was from the current meta-analysis of the Japanese genetic clan studies. For gene-homocysteine association, the outcome of the TT genotypes (vs the CC genotypes) on plasma full homocysteine levels (betahcy/TT) was estimated using the Japanese control subjects from the Tokushima homocysteine written report under a multivariate linear regression model including age and gender as covariates. The effect for the TT genotypes in the gene-homocysteine association was expressed as ane-SD increment in plasma total homocysteine. From these ii estimates, an MR estimate of the effect of plasma total homocysteine on the risk of schizophrenia (ORSCZ/hcy) was calculated every bit follows: log ORSCZ/hcy = (log ORSCZ/TT)/betahcy/TT. The MR guess represented the OR for schizophrenia run a risk per 1-SD increment in plasma total homocysteine. The standard mistake (SE) of the MR approximate was calculated by the Delta method. 54,55
Meta-analysis
The meta-analysis of association studies betwixt the claret homocysteine levels and schizophrenia was performed on the standardized mean differences (SMD). The meta-analysis of association studies between the MTHFR C677T polymorphism and schizophrenia was performed for 5 genetic models, recessive (CC/CT vs TT genotypes), dominant (CC vs CT/TT genotypes), codominant (CC vs TT genotypes), codominant (CT vs TT genotypes), and allele frequency (C-allele vs T-allele), every bit had been washed in a previous study. 45 Heterogeneity was assessed using the I ii statistic. If heterogeneity across studies was found, and so a random-effects model was applied; otherwise, a fixed-effects model was applied. Publication bias was assessed using funnel plots and a regression test. 56 OR and 95% CI were calculated past "metafor," an R package.
Results
Differences in the Plasma Total Homocysteine Levels Betwixt Patients With Schizophrenia and Controls
A linear regression assay showed meaning effects of diagnosis (college in schizophrenic patients than in controls), MTHFR C677T genotypes (college in CT carriers than in CC carriers, and higher in TT carriers than in CC carriers), age (decreases with age), and gender (higher in males than in females) on the plasma total homocysteine levels (diagnosis P = 3.4 × 10–29, genotype P [CT vs CC] = four.7 × 10–three, genotype P [TT vs CC] = 5.viii × 10–43, age P = i.0 × 10–2, and gender P = 1.3 × 10–26). Next, an ANCOVA was performed to examine the presence of the differences between the 2 groups in the plasma full homocysteine separately by gender and by the 3 MTHFR C677T genotypes (total of half-dozen strata), and a meaning effect of diagnosis (college in patients with schizophrenia than in the command) was notwithstanding observed in all strata (diagnosis P of male-genotype CC = 2.4 × 10–8, diagnosis P of male-genotype CT = 3.2 × 10−10, diagnosis P of male-genotype TT = ii.three × 10–4, diagnosis P of female-genotype CC = 1.1 × 10–8, diagnosis P of female-genotype CT = three.two × 10–viii, and diagnosis P of female-genotype TT = 1.2 × 10–5, respectively) subsequently adjustment for age (figure 1).
Fig. ane.
Differences in the plasma total homocysteine levels between patients with schizophrenia and controls separately by gender and past the methylenetetrahydrofolate reductase (MTHFR)C677T genotypes. The ANCOVA demonstrated that the plasma total homocysteine levels were significantly higher in patients with schizophrenia than in controls in each of the six strata (*age-adjusted P < .001).
Fig. 1.
Differences in the plasma total homocysteine levels between patients with schizophrenia and controls separately by gender and by the methylenetetrahydrofolate reductase (MTHFR)C677T genotypes. The ANCOVA demonstrated that the plasma total homocysteine levels were significantly college in patients with schizophrenia than in controls in each of the 6 strata (*historic period-adjusted P < .001).
A Meta-analysis of the Blood Homocysteine Levels in Schizophrenia
We performed a meta-analysis of previous association studies between the claret homocysteine levels and schizophrenia separately by gender. The studies included in this meta-analysis are shown in the supplementary tabular array i. For the meta-analysis of males, data were obtained from 12 association studies, 5,6,8,10,11,13,17,20,21,25,28 including our data, for a total of 1079 patients with schizophrenia and 1559 control subjects. As shown in effigy 2A, the random-effects model showed that the blood homocysteine levels were significantly higher in male patients with schizophrenia than in the male controls (SMD = 0.76; 95% CI = 0.thirty–1.22; P = 1.ii × 10–3) with significant heterogeneity among studies (I two = 96.three%; P < .05). The funnel plot analysis indicated no evidence of publication bias in the male association studies (P = .13; supplementary effigy ane). For the meta-analysis of females, data were obtained from 10 association studies, 5,6,8,10,11,13,17,25,28 including our data, for a total of 615 patients with schizophrenia and 1461 control subjects. Every bit shown in figure 2B, the random-furnishings model showed that the blood homocysteine levels were significantly higher in female patients with schizophrenia than in the female person controls (SMD = 0.fifty; 95% CI = 0.31–0.70; P = 5.9 × 10–seven) with significant heterogeneity amid the studies (I ii = 65.7%; P < .05). The funnel plot analysis indicated no evidence of publication bias in the female association studies (P = .73; supplementary effigy 2).
Fig. two.
![Meta-analyses of association studies between the blood homocysteine levels and schizophrenia. (A) The result of the meta-analysis of 12 male association studies (N = 2638). The blood homocysteine levels were significantly higher in male patients with schizophrenia than in the male controls (standardized mean difference [SMD] = 0.76; 95% CI = 0.30–1.22; P = 1.2×10–3 in the random-effects model). (B) The result of the meta-analysis of 10 female association studies (N = 2076). The blood homocysteine levels were significantly higher in female patients with schizophrenia than in the female controls (SMD = 0.50; 95% CI = 0.31–0.70; P = 5.9×10–7 in the random-effects model).](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/schizophreniabulletin/40/5/10.1093_schbul_sbt154/1/m_schbul_sbt154_f0002.gif?Expires=1648896764&Signature=bUbabF4kAH~zWQ6Zzw9r~h1gdWfIGphsyDNam4t5kZoLHAP6HhV2njt45mJhHqRGSfSK7vA27XBCTBJNeGR9DpeQerVUsbmROpBUtWfmn3AhUtWJfjA75cysXgHmc-yssBD2O6I-TrimugZwYP3RKQBGCni6OavkegUQShiPcWVw7t4bS5Bok-ritJ5gB4B0iKaI1nQZq9KRQMvo2oBSSDsfkIxPnS-P5GvkwfeHUfWWCfohASFWdZH1OcgzXCpTAWq5JEn4fa9PuiezOzgH1QnyGECsuP7anjhZIpu4eVxzRz9HsMUIGo3m~I9mFG7f99GvJrEFYiC8Hwtt49wlRg__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Meta-analyses of association studies between the blood homocysteine levels and schizophrenia. (A) The outcome of the meta-analysis of 12 male person association studies (North = 2638). The claret homocysteine levels were significantly higher in male person patients with schizophrenia than in the male controls (standardized mean difference [SMD] = 0.76; 95% CI = 0.30–one.22; P = 1.two×10–three in the random-furnishings model). (B) The result of the meta-analysis of 10 female association studies (N = 2076). The claret homocysteine levels were significantly college in female patients with schizophrenia than in the female controls (SMD = 0.50; 95% CI = 0.31–0.70; P = 5.ix×10–7 in the random-furnishings model).
Fig. 2.
Meta-analyses of association studies betwixt the blood homocysteine levels and schizophrenia. (A) The result of the meta-analysis of 12 male association studies (N = 2638). The blood homocysteine levels were significantly higher in male patients with schizophrenia than in the male controls (standardized mean difference [SMD] = 0.76; 95% CI = 0.xxx–1.22; P = 1.2×10–3 in the random-furnishings model). (B) The effect of the meta-assay of x female person association studies (N = 2076). The blood homocysteine levels were significantly college in female patients with schizophrenia than in the female controls (SMD = 0.fifty; 95% CI = 0.31–0.lxx; P = v.9×ten–seven in the random-effects model).
A Case-Control Association Study Betwixt the MTHFR C677T Polymorphism and Schizophrenia
Two case-control data sets were evaluated: one is the Tokushima sample gear up (case = 1149, control = 2742), and the other is the Osaka sample set (case = 621, control = 486). The genotypic distributions of rs1801133 did not deviate significantly from the Hardy-Weinberg equilibrium (HWE) in the command groups of these 2 sample sets (P > .05). Significant divergence was observed between the controls and patients with schizophrenia in the allelic frequencies of the Tokushima sample ready (P = .025). On the other mitt, no significant differences were observed in the genotypic and allelic frequencies of the Osaka sample prepare (genotype P = .98, and allele P = .97, respectively).
A Meta-analysis of Genetic Clan Studies Between the MTHFR C677T Polymorphism and Schizophrenia
Six association studies on Japanese subjects, including the ii data sets from this study, were used for the meta-assay. 37–40 The genotypic distributions and allelic frequencies of rs1801133 in each written report are shown in the supplementary table 2. The diagnosis of schizophrenia was made according to DSM-IV criteria in five studies, and information technology was fabricated according to DSM-Three criteria in the remaining study. A total of 4316 cases and 6062 controls were included in this assay. Genotypic distribution of this SNP did non deviate significantly from the HWE in any control group across the 6 studies (P > .05). Significant heterogeneity was not detected at this SNP among the studies for the 5 genetic models (P > .05). The funnel plot analysis indicated no prove of publication bias for all genetic models (P > .05). The results of ORs and CI analyzed past the fixed-effects model for all genetic models and the risk of schizophrenia are shown in table 1. Of these 5 genetic models, significant associations were institute in 4 models. The highest OR was observed in the codominant model (CC vs TT genotypes; figure 3; OR = one.sixteen, 95% CI = 1.03–1.31, P = one.4 × x–2, in the fixed-furnishings model).
Table i.
The Results of OR and 95% CI Analyzed past the Fixed-Effects Model for All Genetic Models and Each P Value in the Meta-analysis for Methylenetetrahydrofolate reductase C677T
| Model | OR | 95% CI | P Value |
|---|---|---|---|
| Recessive (CC/CT vs TT) | one.14 | i.03–1.27 | .016 |
| Dominant (CC vs CT/TT) | one.06 | 0.98–ane.sixteen | .147 |
| Codominant (CC vs TT) | 1.xvi | 1.03–1.31 | .014 |
| Codominant (CT vs TT) | 1.13 | 1.00–1.26 | .042 |
| Allelic (C vs T) | 1.07 | 1.01–ane.13 | .022 |
| Model | OR | 95% CI | P Value |
|---|---|---|---|
| Recessive (CC/CT vs TT) | 1.14 | one.03–ane.27 | .016 |
| Ascendant (CC vs CT/TT) | one.06 | 0.98–1.16 | .147 |
| Codominant (CC vs TT) | 1.xvi | 1.03–1.31 | .014 |
| Codominant (CT vs TT) | 1.13 | one.00–1.26 | .042 |
| Allelic (C vs T) | 1.07 | 1.01–1.13 | .022 |
Tabular array 1.
The Results of OR and 95% CI Analyzed by the Fixed-Effects Model for All Genetic Models and Each P Value in the Meta-analysis for Methylenetetrahydrofolate reductase C677T
| Model | OR | 95% CI | P Value |
|---|---|---|---|
| Recessive (CC/CT vs TT) | i.xiv | ane.03–1.27 | .016 |
| Dominant (CC vs CT/TT) | ane.06 | 0.98–1.sixteen | .147 |
| Codominant (CC vs TT) | 1.xvi | 1.03–1.31 | .014 |
| Codominant (CT vs TT) | 1.xiii | i.00–1.26 | .042 |
| Allelic (C vs T) | one.07 | 1.01–1.13 | .022 |
| Model | OR | 95% CI | P Value |
|---|---|---|---|
| Recessive (CC/CT vs TT) | 1.14 | i.03–1.27 | .016 |
| Dominant (CC vs CT/TT) | one.06 | 0.98–ane.16 | .147 |
| Codominant (CC vs TT) | 1.16 | one.03–1.31 | .014 |
| Codominant (CT vs TT) | i.13 | ane.00–one.26 | .042 |
| Allelic (C vs T) | one.07 | 1.01–1.thirteen | .022 |
Fig. 3.
A meta-assay of genetic association studies on Japanese subjects between the MTHFR C677T polymorphism and schizophrenia. Six association studies on Japanese subjects, including the 2 data sets from this study, were used for the meta-analysis (North = 10 378). Pregnant associations between the MTHFR C677T polymorphism and schizophrenia were found in iv models, and the result of the codominant model (CC vs TT genotypes) is shown (OR = one.sixteen, 95% CI = 1.03–1.31, P = 1.4×10–2 in the stock-still-effects model).
Fig. iii.
A meta-analysis of genetic clan studies on Japanese subjects between the MTHFR C677T polymorphism and schizophrenia. Six association studies on Japanese subjects, including the 2 data sets from this study, were used for the meta-assay (N = 10 378). Significant associations between the MTHFR C677T polymorphism and schizophrenia were establish in 4 models, and the result of the codominant model (CC vs TT genotypes) is shown (OR = i.xvi, 95% CI = i.03–one.31, P = 1.4×10–2 in the fixed-effects model).
Upshot of Plasma Total Homocysteine Levels on Schizophrenia Risk in an MR Written report
From the current meta-analysis of the Japanese genetic association studies, the pooled OR (the TT vs CC genotypes) for the issue of the MTHFR C677T polymorphism on schizophrenia take chances was i.sixteen (95% CI = 1.03–1.31). In multivariate gene-homocysteine association analysis in the Japanese control subjects genotyped (n = 980 with a SD for plasma total homocysteine levels of iv.84 nmol/ml), the effect on plasma total homocysteine levels, expressed as 1-SD increment in homocysteine, was estimated to be 1.xiv (95% CI = 0.96–1.33; P = 1.1 × 10–29) for the TT genotypes of the MTHFR C677T polymorphism (vs the CC genotypes), later on adjustment for age and gender. When combining these 2 estimates past an MR approach, the effect of plasma total homocysteine on schizophrenia take chances was statistically significant, representing the OR of 1.fourteen (95% CI = 1.03–1.27; P = 1.6 × 10–2) for schizophrenia per one-SD increment in plasma total homocysteine (figure iv).
Fig. 4.
Graphical representation of the mendelian randomization approach. The pooled OR (the TT vs CC genotypes) for the consequence of the MTHFR C677T polymorphism on schizophrenia take chances was one.16 (95% CI = i.03–ane.31). The OR (the TT vs CC genotypes) for the effect of the MTHFR C677T polymorphism on plasma total homocysteine levels, expressed as one-SD increase in homocysteine, was i.14 (95% CI = 0.96–i.33; P = 1.1×10–29). The effect of plasma full homocysteine on schizophrenia chance past a mendelian randomization analysis was statistically significant, representing the OR of 1.14 (95% CI = 1.03–i.27; P = 1.six×10–ii) for schizophrenia per ane-SD increase in plasma total homocysteine.
Fig. 4.
Graphical representation of the mendelian randomization approach. The pooled OR (the TT vs CC genotypes) for the effect of the MTHFR C677T polymorphism on schizophrenia run a risk was 1.16 (95% CI = 1.03–ane.31). The OR (the TT vs CC genotypes) for the effect of the MTHFR C677T polymorphism on plasma total homocysteine levels, expressed equally 1-SD increase in homocysteine, was i.14 (95% CI = 0.96–1.33; P = 1.1×10–29). The issue of plasma total homocysteine on schizophrenia take chances past a mendelian randomization analysis was statistically significant, representing the OR of one.14 (95% CI = 1.03–ane.27; P = ane.six×10–ii) for schizophrenia per ane-SD increase in plasma total homocysteine.
Discussion
In this study, we performed an association study between the plasma total homocysteine and schizophrenia with stratification by gender and past the MTHFR C677T genotypes and demonstrated significantly elevated plasma full homocysteine levels in patients with schizophrenia compared with controls, in both male and female subjects. The subsequent meta-analysis for gender supported this finding. To our noesis, this is the first written report to bear a meta-assay according to gender. The significant decrease in plasma full homocysteine levels with historic period in our multivariate linear regression analysis was not consistent with a previous finding. 33 This discrepancy might exist caused past disease status and gender of the subjects analyzed. When we examined the relationship between age and the plasma total homocysteine levels in a univariate linear regression model, a significant negative correlation was observed only in male person subjects with schizophrenia ( supplementary figure 3). Consistent with this finding, Levine et al 5 reported that the difference in the plasma total homocysteine levels betwixt patients and controls was attributable to young male person patients with schizophrenia.
We also conducted a meta-assay of genetic association studies between the MTHFR C677T polymorphism and schizophrenia based on Japanese subjects and demonstrated that the MTHFR C677T polymorphism was a risk factor for developing schizophrenia in the Japanese population, which is consistent with the results of previous meta-analyses. 39,41–47,57 On the other hand, this polymorphism has not been identified as a gamble locus for schizophrenia in the large genome-wide association studies. 58,59 This discrepancy might exist acquired past ethnic differences (risk allele [T] frequencies from HapMap; Japanese 0.39, Caucasian 0.31, African American 0.12, and Mexican American 0.41) and a lack of adequate statistical power to detect the relatively pocket-size genetic effect of this polymorphism on schizophrenia at the genome-wide significant threshold.
Importantly, we demonstrated that increased homocysteine levels may exist associated with an increased adventure of developing schizophrenia by an MR approach. Hyperhomocysteinemia has been proposed as being role of the pathophysiology of schizophrenia due to its diverse biological furnishings, such every bit interim as a partial antagonist of the glutamate site of the N-methyl-d-aspartate receptor 23 and causing subtle placental vascular damage that interferes with oxygen commitment to the fetus, lx DNA damage and prison cell cytotoxicity, 61 neuronal apoptosis, 62 and mitochondrial nitric oxide accumulation. 63 Homocysteine acts every bit a methyl donor when information technology is converted to Due south-adenosyl-methionine, and nosotros recently demonstrated a meaning association between the plasma full homocysteine and DNA methylation in schizophrenia, which suggests that homocysteine might play a office in the pathogenesis of schizophrenia via alterations to DNA methylation. 64 Homocysteine, S-adenosyl-methionine, DNA methylation, MTHFR, folate, and vitamin B12 are involved in one-carbon metabolism, and abnormalities of these components in schizophrenia have been reported in previous studies. 2,3,65 These lines of evidence advise that disrupted 1-carbon metabolism may be an important office in the pathophysiology of schizophrenia.
The benefits of homocysteine-reducing strategies in schizophrenia have been shown in several studies. Levine et al 66 reported an comeback in the clinical symptoms of schizophrenic patients with hyperhomocysteinemia who were treated with folate, vitamin B12, and pyridoxine. Hill et al 67 reported an comeback in the negative symptoms of schizophrenic patients who were treated with folate when the MTHFR C677T genotype was taken into account. Roffman et al 68 reported an comeback in the negative symptoms of schizophrenic patients who were treated with folate and vitamin B12 when four variants in the FOLH1, MTHFR, MTR, and COMT genes were taken into account. Further research volition be necessary to place the features of patients with schizophrenia who would benefit from homocysteine-reducing treatments. In cardiovascular diseases, which are too associated with hyperhomocysteinemia, clinical trials to identify a subgroup that appeared to do good from homocysteine-lowering intervention have been performed 69,70 although no benefits of homocysteine-lowering intervention on cardiovascular outcomes accept been reported in randomized controlled trials. 71
Many studies have indicated the potential contributions of the MTHFR C677T polymorphism to the pathophysiology of schizophrenia. This chance SNP has been associated with schizophrenic negative symptoms, aggressive behavior, and various phenotypes related to schizophrenia, such as cerebral function, episodic retentivity, grayness matter density, and prefrontal role. 72–eighty Interestingly, pharmacogenetic studies have demonstrated that this hazard SNP has also been involved in the antipsychotic drug response and metabolic syndrome treated with antipsychotics in schizophrenia. 81–84
There are some limitations to this study. First, we did non obtain genomic DNA from all participants in the association study between the plasma total homocyateine levels and schizophrenia. Second, all patients were treated with various antipsychotic drugs, and these medications might influence the outcome. When nosotros examined the relationship betwixt equivalent dose and the plasma full homocysteine levels in subjects with schizophrenia by a univariate linear regression model, a positive correlation was observed in female subjects (P = .03). However, it did not attain statistical significance afterwards correction for multiple comparisons. 3rd, there was heterogeneity amidst the studies in the meta-analysis for blood homocysteine, while pregnant heterogeneity was not observed in the meta-assay for genetic association studies. This heterogeneity might be caused past other genetic variations, the clinical heterogeneity of the patients included, medications, and environmental factors, such as folic acid, vitamin B6, vitamin B12, obesity, smoking status, and caffeine consumption, although we did non accept these confounding factors into consideration in our analysis. Fourth, the use of "well controls" in this case-control analysis might accentuate such misreckoning influences. 85 Fifth, this is a cross-exclusive study, and MR has limitations on the ability to establish causal relationships between gamble factors and outcomes. 86 So, the causality between schizophrenia and blood homocysteine levels must be still cautious. Notably, elevated maternal levels of homocysteine during the third trimester have been found to increase the risk of schizophrenia in the offspring. 60 Finally, hyperhomocysteinemia has been identified equally an contained chance factor for several neurological disorders in improver to schizophrenia, such as depression and dementia. 87,88 Further studies to examine how hyperhomocysteinemia is involved in the pathophysiology of each affliction will be necessary.
In decision, to the best of our cognition, this is the first meta-analysis of association studies between blood homocysteine levels and schizophrenia according to gender, and we demonstrated elevated blood homocysteine levels in both male and female subjects with schizophrenia. The meta-analysis of genetic association studies using the Japanese subjects provided stringent evidence of clan between the MTHFR C677T polymorphism and schizophrenia. Our MR analysis using the Japanese subjects suggests that increased plasma total homocysteine levels may be associated with an increased take a chance of developing schizophrenia.
Funding
Core Research for Evolutional Scientific discipline and Technology, Japan Science and Engineering Bureau; Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (24791216); SENSHIN Medical Research Foundation; Research Grouping For Schizophrenia.
Acknowledgments
The authors would similar to thank all of the volunteers who understood the purpose of our study and participated in this report, also as the physicians who helped usa to collect clinical data and blood samples at the mental hospitals. The authors would too like to give thanks Mrs Akemi Okada for her technical assistance. All authors report no biomedical financial interests or potential conflicts of involvement.
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