title: Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?
abstract: Past analyses examining the relationship between genetic variation in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene and psychiatric disorders have provided mixed and largely inconclusive findings. MTHFR is involved in the one-carbon metabolic pathway which is essential for DNA biosynthesis and the epigenetic process of DNA methylation. We conducted a meta-analysis of all published case-control studies investigating associations between two common MTHFR single nucleotide polymorphisms (SNPs), MTHFR C677T (sample size 29,502) and A1298C (sample size 7934), and the major psychiatric disorders (i) schizophrenia (SZ), (ii) bipolar disorder (BPD), and (iii) unipolar depressive disorder (UDD). In order to examine possible shared genetic vulnerability, we also tested for associations between MTHFR and all of these major psychiatric disorders (SZ, BPD and UDD) combined. MTHFR C677T was significantly associated with all of the combined psychiatric disorders (SZ, BPD and UDD); random effects odds ratio (OR)=1.26 for TT versus CC genotype carriers; confidence interval (CI) 1.09-1.46); meta-regression did not suggest moderating effects of psychiatric diagnosis, sex, ethnic group or year of publication. Although MTHFR A1298C was not significantly associated with the combination of major psychiatric disorders, nor with SZ, there was evidence for diagnostic moderation indicating a significant association with BPD (random effects OR=2.03 for AA versus CC genotype carriers, CI: 1.07-3.86). Meta-analysis on UDD was not possible due to the small number of studies available. This study provides evidence for shared genetic vulnerability for SZ, BPD and UDD mediated by MTHFR 677TT genotype, which is in line with epigenetic involvement in the pathophysiology of these psychiatric disorders.
authors.affiliation: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, European Graduate School of Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University, Maastricht, The Netherlands.
authors.forename: Odette L J
authors.initials: OL
authors.lastname: Peerbooms
authors.forename: Jim
authors.initials: J
authors.lastname: van Os
authors.forename: Marjan
authors.initials: M
authors.lastname: Drukker
authors.forename: Gunter
authors.initials: G
authors.lastname: Kenis
authors.forename: Loes
authors.initials: L
authors.lastname: Hoogveld
authors.forename: Marc
authors.initials: M
authors.lastname: de Hert
authors.forename: Philippe
authors.initials: P
authors.lastname: Delespaul
authors.forename: Ruud
authors.initials: R
authors.lastname: van Winkel
authors.forename: Bart P F
authors.initials: BP
authors.lastname: Rutten
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D016001:Confidence Intervals; D003627:Data Interpretation, Statistical; D003866:Depressive Disorder / Q000235:genetics*; D057890:Epigenomics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D015810:Linkage Disequilibrium; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D016017:Odds Ratio; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2)