Meta-analysis Report

Reference	Gilbody, S., 2007 PMID: 17074966
Citation	Gilbody, S., S. Lewis, et al. (2007). "Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review." Am J Epidemiol 165(1): 1-13.
Disease Type	Bipolar Disorder & Major Depressive Disorder & Schizophrenia
Study Type	Candidate-gene association study

Samples	For unipolar depression and the MTHFR C677T polymorphism, searches identified 10 studies (11,709 participants; 1,280cases of depression, 10,429 controls). For schizophrenia and MTHFR C677T, searches identified 12 studies (6,125 participants; 2,762 cases of schizophrenia, 3,363 controls). For bipolar disorder and MTHFR C677T, searches identified four studies (1,648 participants; 550 cases of bipolar disorder, 1,098 controls).
Statistic Method	We combined odds ratios using both fixed-effects and random-effects models In subgroup analyses, we estimated race-specific odds ratios for each allele contrast. We also performed cumulative meta-analysis to evaluate whether the association changed over time. We estimated between-study heterogeneity using the I2 statistic. To test for publication bias, we applied funnel plot analysis and a regression test. Where analyses were stratified by race, quality, disequilibrium, or diagnostic method, we tested for relations between study-level variables and relations between odds ratios by means of logistic meta-regression, using a permutation test (with 1,000 Monte Carlo simulations) to calculate p values and to reduce the chance of spurious false-positive findings. The amount of heterogeneity explained by the use of predictive covariates was examined by reductions in the I2 inconsistency statistic.
Basic Result	For unipolar depression and the MTHFR C677T polymorphism, the fixed-effects odds ratio for homozygote variants (TT) versus the wild type (CC) was 1.36 (95%confidence interval (CI): 1.11, 1.67), with no residual between-study heterogeneity (I2= 0%)—based on 1,280 cases and 10,429 controls. For schizophrenia and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.44 (95% CI: 1.21, 1.70), with low heterogeneity (I2= 42%)—based on 2,762 cases and 3,363 controls. For bipolar disorder and MTHFR C677T, the fixed-effects odds ratio for TT versus CC was 1.82 (95% CI: 1.22, 2.70), with low heterogeneity (I2= 42%)—based on 550 cases and 1,098 controls. These results were robust to various sensitively analyses. This meta-analysis demonstrates an association between the MTHFR C677T variant and depression, schizophrenia, and bipolar disorder, raising the possibility of the use of folate in treatment and prevention.