Genetic polymorphisms in methylenetetrahydrofolate reductase C677T and schizophrenia risk: a Meta-analysis on case-control study

Abstract

Objective To evaluate the hereditary relation of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR）C677T with the risk of schizophrenia. Methods According to established strategy and selection criteria and exclusion criteria, a search had been performed on Chinese Wanfang Database, Chinese National Knowledge Infrastructure and Database，Chongqing VIP Database for Chinese Technical Periodicals, PubMed, Embase, Schizophrenia-Gene and HuGENet to identify all the case-control studies associated with MTHFR C677T genetic polymorphisms and schizophrenia. Hand searches of cross references were also conducted for further references．The quality of included studies was evaluated by Strengthening the Reporting of Genetic Association Studies (STREGA). In addition to common meta-analysis, cumulative meta-analysis, regressive meta-analysis, subgroup analysis, sensitive analysis and publication bias testing were used to analyze the data． Results Twenty-eight eligible studies with moderate to obvious heterogeneity were included, involving total 7 257 cases and 8 900 controls. There were significant associations between C677T polymorphisms and schizophrenia risk throughout whole populations by T-allele vs. C-allele (odds ratio, OR; OR= 1.15, Z=3.53, P=0.000) and by TT-genotype vs. CC-genotype (OR= 1.37, Z=3.63, P=0.000), but not by CT-genotype vs. CC-genotype (OR= 1.10, Z=1.86, P=0.064). Since the regressive meta-analysis demonstrated most studies from China accounted for the whole heterogeneity by 68.74% (t=3.69, P=0.001), a further subgroup-analysis was carried out to show that TT-genotype relative to CC-genotype led to significantly higher risks of schizophrenia throughout the Chinese-subgroup(OR= 4.12, Z=5.27, P=0.000) and non-Chinese subgroup(OR= 1.25, Z=2.92, P=0.003), while CT-genotype only in Chinese-subgroup(OR = 2.18, Z=3.84, P=0.000). As stratified by gender, only male-subgroup who carried TT-genotype represented a significant association (TT vs. CC: OR= 1.51, Z=2.55, P=0.011). The performed meta-analyses showed consistent results to cumulative meta-analysis and sensitive analysis, and no evidence of publication bias by Begg′s test (Z=1.46，P=0.143) and Egger′s test (t=1.96，P=0.060). Conclusion The study provides evidence for a hereditary associations between the MTHFR C677T variant and schizophrenia risk, however it is obviously various between different regions, ethnicities and genders. Key words: Schizophrenia; Genes; Methylenetetrahydrofolate reductase(NADPH2); Polymorphism，single nucleotide; Meta-analysis