Meta-analyses of Blood Homocysteine Levels for Gender and Genetic Association Studies of the MTHFR C677T Polymorphism in 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 have 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, we conducted a meta-analysis of association studies between blood homocysteine levels and schizophrenia separately by gender (N = 4714). Third, we performed a case-control association study between the MTHFR C677T polymorphism and schizophrenia (N = 4998) and conducted a meta-analysis of genetic association studies based on Japanese subjects (N = 10 378). Finally, we assessed the effect of plasma total homocysteine levels on schizophrenia by a mendelian randomization approach. The ANCOVA after adjustment for age demonstrated a significant effect 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 outcome. The meta-analysis of the Japanese genetic association studies demonstrated a significant association between the MTHFR C677T polymorphism and schizophrenia. The mendelian randomization analysis in the Japanese populations yielded an OR of 1.15 for schizophrenia per 1-SD increase in plasma total homocysteine. Our study suggests that increased plasma total homocysteine levels may be associated with an increased risk of schizophrenia.

Decreased serum pyridoxal levels in schizophrenia: meta-analysis and Mendelian randomization analysis

“…For example, we observed elevated blood homocysteine levels in individuals with schizophrenia and provided evidence of a causal relationship between elevated blood homo-cysteine levels and schizophrenia risk. 6,7 In addition, we showed that the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which causes reduced enzyme activity and elevated homocysteine levels, and common polygenic variants that are associated with plasma homo cysteine levels are risk factors for schizophrenia in the Japanese population. 6,8 Furthermore, we showed aberrant DNA methylation in patients with schizophrenia, not only in peripheral leukocytes but also in the postmortem dorsolateral prefrontal cortex.…”

“…6,7 In addition, we showed that the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which causes reduced enzyme activity and elevated homocysteine levels, and common polygenic variants that are associated with plasma homo cysteine levels are risk factors for schizophrenia in the Japanese population. 6,8 Furthermore, we showed aberrant DNA methylation in patients with schizophrenia, not only in peripheral leukocytes but also in the postmortem dorsolateral prefrontal cortex. [9][10][11] Vitamin B6 is a key component in one-carbon metabolism, in which homocysteine enters the transsulfuration pathway that leads to the production of cysteine and glutathione.…”

Effects of second-generation antipsychotics on selected markers of one-carbon metabolism and metabolic syndrome components in first-episode schizophrenia patients

“…Two previous meta-analyses including studies on various subgroups of patients indicated that increased Hcy level is associated with higher schizophrenia risk [12, 13]. Several mechanisms may underlie causative links between OCM disturbances and schizophrenia.…”

Genetics of Common Antipsychotic-Induced Adverse Effects

“…The attenuation of MTHFR as a consequence of these SNPs has been linked to elevated plasma homocysteine. Hyperhomocysteinemia has been associated with a greater risk of both SCZ and cardiovascular disease [103,104,105]. Taken together, there is a rationale establishing MTHFR as a potential candidate influencing AAEs.…”