title: Evaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis.
abstract: BACKGROUND
  The results of meta-analyses conducted by previous association studies between total homocysteine and schizophrenia suggest that an elevated total homocysteine level is a risk factor for schizophrenia. However, observational studies have potential limitations, such as confounding and reverse causation. In the present study, we evaluated a causal relationship between plasma total homocysteine and schizophrenia by conducting a Mendelian randomization analysis.
  
  
  METHODS
  We used the MTHFR C677T polymorphism as an instrumental variable, which affects the plasma total homocysteine levels. To calculate the risk estimate for the association of this single nucleotide polymorphism (SNP) with schizophrenia, we conducted a meta-analysis of case-control studies that comprise a total of 11,042 patients with schizophrenia and 14,557 control subjects. We obtained an estimate for the association of this SNP with the plasma total homocysteine levels from a meta-analysis of genome-wide association studies comprising 44,147 individuals.
  
  
  RESULTS
  By combining these two estimates, we demonstrated a significant effect of the plasma total homocysteine on schizophrenia risk, representing an OR of 2.15 (95 % CI = 1.39-3.32; p = 5.3 x 10(-4)) for schizophrenia per 1-SD increase in the natural log-transformed plasma total homocysteine levels.
  
  
  CONCLUSIONS
  We provided evidence of a causal relationship between the plasma total homocysteine and schizophrenia, and this result will add insight into the pathology and treatment of schizophrenia.
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan. shu-numata@umin.ac.jp.
authors.forename: Shusuke
authors.initials: S
authors.lastname: Numata
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan. knst5511mkt@sunny.ocn.ne.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Bioinformatics and Genomics, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takawamachi, Kanazawa, Ishikawa, 920-8640, Japan. atajima@med.kanazawa-u.ac.jp.|Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan. atajima@med.kanazawa-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan. aovestn@gmail.com.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishi
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan. issehgen@tokushima-u.ac.jp.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan. ohmori@tokushima-u.ac.jp.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ohmori
mesh_terms: D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D057182:Mendelian Randomization Analysis; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics*
chemical_list: D006710:Homocysteine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)