One-carbon metabolism is a process whereby folate transfers one-carbon groups in a range of biological processes, including DNA methylation and homocysteine metabolism. We have focused on and examined the potential roles of this one-carbon metabolism in the pathology of schizophrenia. Firstly, we revealed that aberrant DNA methylation in schizophrenia occurred across the whole genome in peripheral leukocytes by conducting genome-wide DNA methylation profiling. Secondly, we demonstrated that plasma total homocysteine was associated with DNA methylation in patients with schizophrenia at specific genes. Thirdly, we demonstrated that blood homocysteine levels were significantly higher in patients with schizophrenia than in non-psychiatric controls by conducting meta-analysis of previous observational studies. Fourthly, we demonstrated a causal relationship between blood homocysteine and schizophrenia by conducting Mendelian randomization analysis. Finally, we demonstrated that the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, which causes reduced enzyme activity and higher homocysteine levels, was a risk factor for developing schizophrenia in a Japanese population by conducting meta-analysis of previous genetic association studies. These results will add new insights into the pathology and treatment of schizophrenia.
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