C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies

A meta-analysis of the previous studies of allelic association between schizophrenia, bipolar disorder and depression with the C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene was carried out. Attention was paid to genetic differences in ancestral groups. Ten studies of the C677T MTHFR polymorphism and schizophrenia were included, along with four studies with the A1298C MTHFR polymorphism and schizophrenia. Four association studies of the C677T MTHFR polymorphism with bipolar disorder, and five studies of the C677T base pair change with depression were included. The studies contained Caucasian and east Asian samples. For schizophrenia, the main analysis for investigating the association of the C677T allele T and the risk of developing schizophrenia relative to the allele C showed lack of heterogeneity (P=0.22,I-2=24%) between samples. In these samples, the fixed effects odds ratio was marginally significant [odds ratio 1.13 (95% confidence interval, 1.04-1.23)]. In an analysis of subgroups, the odds ratio were not significant for the Caucasian sample [random effects odds ratio 1.14 (0.95-1.36) and fixed effects odds ratio 1.13 (1.00-1.27)](P=0.14, I-2 = 43%) and in Asians [random effects odds ratio 1.15 (0.98-1.35) and fixed effects odds ratio 1.15 (1.01-1.31)] (P=0.19,I-2=37). The recessive model for allele T produced significant results in the main analysis [fixed effects odds ratio 1.32 (1.12-1.56A in east Asians [fixed effects odds ratio 1.45 (1.13-1.85)] and female participants [fixed effects odds ratio 1.70 (1.07-2.71)], whereas for Caucasians the results were nonsignificant. For the A1298C polymorphism, in the main analysis the allele frequency difference between C and A, and the dominant model for allele C produced marginally significant associations [fixed effects odds ratio 1.16 (1.03-1.31) and fixed effects odds ratio 1.19 (1.02-1.40), respectively]. In bipolar disorder, overall, there was no significant association between either allele of the C677T polymorphism and the risk of developing bipolar disorder. Only in the east Asian population was the C677T association of marginal significance, with fixed effects odds ratio 1.23 (1.00-1.52). No sources of potential bias were found in the selected studies. The meta-analysis results suggested that east Asians have a greater genetic risk from the MTHFR gene in developing schizophrenia and depression, and that the genetic effects in bipolar disorder and depression are different. A further exploration of the involvement of the MTHFR gene in the susceptibility to schizophrenia and affective disorders, with a greater number of studies with larger sample sizes, however, are needed to fully establish the role of the MTHFR gene.