title: Gene-wide association study between the methylenetetrahydrofolate reductase gene (MTHFR) and schizophrenia in the Japanese population, with an updated meta-analysis on currently available data.
abstract: Methylenetetrahydrofolate reductase (MTHFR) is a critical molecule for single-carbon transfer reactions. Recent evidence suggests that polymorphisms of MTHFR are related to neural tube deficits and the pathogenesis of schizophrenia. While several studies have demonstrated associations between the gene encoding the MTHFR (MTHFR) polymorphisms and schizophrenia, these studies lack consistency. Therefore, we conducted a gene-wide association study (patients with schizophrenia = 696, control subjects = 747) and performed imputation analysis. Additionally, we performed meta-analysis on currently available data from 18 studies for two common functional polymorphisms (rs1801131 and rs1801133). There were no significant associations with schizophrenia in the single marker analysis for the seven tagging SNPs of MTHFR. In the haplotypic analysis, a nominally significant association was observed between the haplotypes, which included four SNPs (rs1801133, rs17421511, rs17037396, and rs9651118) and the schizophrenic patients. Additionally, the imputation analysis demonstrated there were several associated markers on the MTHFR chromosomal region. However, confirmatory analyses of three tagging SNPs (rs1801133, rs17037396, and rs9651118) and the top SNP (rs17421511) for the imputation results (patients with schizophrenia = 797, control subjects = 1025) failed to replicate the haplotypic analysis and the imputation results. These findings suggest that MTHFR polymorphisms are unlikely to be related to the development of schizophrenia in the Japanese population. However, since our meta-analysis results demonstrated strong support for association of rs1801133 with schizophrenia, further replication studies based on a gene-wide approach need to be considered.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshimi
authors.forename: Branko
authors.initials: B
authors.lastname: Aleksic
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kawamura
authors.forename: Nagahide
authors.initials: N
authors.lastname: Takahashi
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Hinako
authors.initials: H
authors.lastname: Usui
authors.forename: Shinichi
authors.initials: S
authors.lastname: Saito
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Ito
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)