Meta-analysis Report

Reference	Peerbooms, O. L.,2011 PMID: 21185933
Citation	Peerbooms, O. L., J. van Os, et al. (2011). "Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability?" Brain Behav Immun 25(8): 1530-1543.
Disease Type	Bipolar Disorder & Major Depressive Disorder & Schizophrenia
Study Type	Candidate-gene association study

Samples	This meta analysis included data reported in 42 publications describing 51 samples that consisted of 29,502 subjects (9648 patients and 19,854 controls) with genotyping of MTHFR C677T including 36 articles describing 48 samples comprising 22 SZ samples, nine BPD samples and 17 UDD samples and 7934 subjects(3507 patients and 4427 controls) with genotyping of MTHFR A1298C including 13 articles describing a total of 18 samples comprising 13 SZ samples, four BPD samples and one UDD sample.
Statistic Method	Pooled ORs and 95% confidence intervals (CI) were calculated using five genetic models of analysis: model 1 is the recessive genotype model, model 2 is the dominant genotype model, model 3 and 4 are co-dominant genotype models, and model 5 is the allele frequencies model. Heterogeneity between studies was tested using the chi-squared test (cut-off: p < 0.05) and quantified using the I2 metric (which is independent of the number of studies in the meta-analysis).Meta-regression was used to investigate effects of the possible modifiers of diagnosis, sex, ethnic group and year of publication.The following additional tests were used for evaluation of robustness of the results. The distributions of the genotypes in the control groups were tested for Hardy-Weinberg equilibrium using the exact test. Sensitivity analyses were conducted for samples not in Hardy- Weinberg equilibrium (p < 0.05 in the exact test) to evaluate the impact of these studies. In a second sensitivity analysis, we excluded samples with p-values <0.1 in the exact test; this was done because the exact test for Hardy-Weinberg equilibrium may be influenced negatively by small effects and small sample sizes of the included studies (Salanti et al., 2005).
Basic Result	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.