Meta-analysis Report

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Basic Info

Reference	Zintzaras, E., 2006 PMID: 16691128
Citation	Zintzaras, E. (2006). "C677T and A1298C methylenetetrahydrofolate reductase gene polymorphisms in schizophrenia, bipolar disorder and depression: a meta-analysis of genetic association studies." Psychiatr Genet 16(3): 105-115.
Disease Type	Bipolar Disorder & Major Depressive Disorder & Schizophrenia
Study Type	Candidate-gene association study

Detail Info

Samples	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.
Statistic Method	The heterogeneity between studies was tested using the Q-statistic. The pooled OR was estimated using fixed effects (FEs) (Mantel-Haenszel) and random effects (REs) (DerSimonian and Laird) models. A differential magnitude of effect in large vs. small studies (or publication bias) for the allele frequency difference was checked using the Egger regression test for funnel plot asymmetry and the Begg-Mazumdar test. Analyses were performed using meta-analyst, and CVF90 with IMSL Fortran 90 Library version 4.01.
Basic Result	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 (1.12-1.56)] 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.

Genetic factors reported by this study for BD

Other variants reported by this study for BD (count: 1)

Variant Name	Related Gene	Type	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
MTHFR C677T	MTHFR	point mutation	C/T		T vs. C P-value = 0.16 in all, P-value = 0.55 in East Asians, Fixed effects OR (95% CI)=1.11 [0.92-1.33] in all, 1.23 [1.00-1.52] in East Asians; Random effects OR (95% CI)=1.08 [0.84-1.40] in all, 1.23 [1.00-1.52] in East Asians; TT vs. CC P-value = 0.29 in all, P-value = 0.38 in East Asians; Fixed effects OR (95% CI)=1.22 [0.81-1.83] in all, 1.44 [0.90-2.31] in East Asians; Random effects OR (95% CI)=1.18 [0.74-1.90] in all, 1.45 [0.90-2.33] in East Asians; TT vs. (TC+CC) P-value = 0.53 in all, P-value = 0.04 in East Asians; Fixed effects OR (95% CI)=1.19 [0.82-1.75] in all, 1.30 [0.84-2.01] in East Asians; Random effects OR (95% CI)=1.20 [0.82-1.76] in all, 1.31 [0.85-2.02] in East Asians; (TT +TC) vs. CC P-value = 0.12 in all, P-value = 0.60 in East Asians; Fixed effects OR (95% CI)=1.12 [0.87-1.44] in all, 1.32 [0.98-1.77] in East Asians; Random effects OR (95% CI)=1.09 [0.76-1.57] in all, 1.32 [0.98-1.77] in East Asians	Overall, there was no significant association between C677T ...... Overall, there was no significant association between C677T polymorphism and the risk of developing bipolar disorder, and the heterogeneity between studies was moderate. In the east Asian population, the heterogeneity was not significant and the FEs pooled OR was 1.23 (1.00-1.52), which could be considered rather marginal. The remaining genetic contrasts examined produced nonsignificant results, with the dominant model for allele T showing a trend towards association. More...	Positive

Genes reported by this study for BD (count: 1)

Gene	Statistical Values/Author Comments	Result Category
MTHFR	The meta-analysis results suggested that east Asians have a greater genetic risk from the MTHFR gene...... 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. More...	Positive

Genetic factors reported by this study for SZ and/or MDD

Other variants reported by this study for SZ/MDD

Disease	Variant Name	Related Gene	Type	Statistical Values	Description	Result Category
SZ	MTHFR C677T	MTHFR	point mutation	T vs. C: P-value Q-test=0.22, Fixed effects OR (95% CI)=1.13 [1.04-1.23] , Random effects OR (95% CI)=1.14 [1.03-1.25] in all; P-value Q-test=0.2, Fixed effects OR (95% CI)=1.14 [1.05-1.24], Random effects OR (95% CI)=1.15 [1.04-1.27] in all in HWE; P-value Q-test=0.14, Fixed effects OR (95% CI)=1.13 [1.00-1.27], Random effects OR (95% CI)=1.14 [0.95-1.36] in Caucasians; P-value Q-test=0.1, Fixed effects OR (95% CI)=1.14 [1.01-1.29], Random effects OR (95% CI)=1.17 [0.96-1.41] in Cauc. in HWE; P-value Q-test=0.19, Fixed effects OR (95% CI)=1.15 [1.01-1.31], Random effects OR (95% CI)=1.15 [0.98-1.35] in East Asians; P-value Q-test=0.16, Fixed effects OR (95% CI)=1.15 [0.95-1.38], Random effects OR (95% CI)=1.13 [0.87-1.48] in Men; P-value Q-test=0.42, Fixed effects OR (95% CI)=1.17 [0.96-1.43], Random effects OR (95% CI)=1.17 [0.96-1.43] in Women; TT vs. CC: P-value Q-test=0.2, Fixed effects OR (95% CI)=1.34 [1.12-1.60], Random effects OR (95% CI)=1.34 [1.08-1.67] in all; TT vs. CC: P-value Q-test=0.23, Fixed effects OR (95% CI)=1.37 [1.14-1.64], Random effects OR (95% CI)=1.37 [1.11-1.70] in All in HWE ; P-value Q-test=0.16, Fixed effects OR (95% CI)=1.20 [0.92-1.57] , Random effects OR (95% CI)=1.23 [0.84-1.78] in Caucasians; P-value Q-test=0.16, Fixed effects OR (95% CI)=1.25 [0.95-1.65], Random effects OR (95% CI)=1.30 [0.89-1.89] in Cauc. in HWE; P-value Q-test=0.25, Fixed effects OR (95% CI)=1.40 [1.07-1.83], Random effects OR (95% CI)=1.38 [1.00-1.90] in East Asians; P-value Q-test=0.18, Fixed effects OR (95% CI)=1.27 [0.86-1.90], Random effects OR (95% CI)=1.26 [0.74-2.16] in Men; P-value Q-test=0.62, Fixed effects OR (95% CI)=1.64 [1.02-2.66], Random effects OR (95% CI)=1.65 [1.02-2.66] in Women; TT vs. (TC + CC): P-value Q-test=0.19, Fixed effects OR (95% CI)=1.32 [1.12-1.56], Random effects OR (95% CI)=1.31 [1.07-1.61] in all; P-value Q-test=0.28, Fixed effects OR (95% CI)=1.35 [1.14-1.60], Random effects OR (95% CI)=1.35 [1.11-1.63] in All in HWE; P-value Q-test=0.31, Fixed effects OR (95% CI)=1.10 [0.85-1.41], Random effects OR (95% CI)=1.11 [0.83-1.48] in Caucasians; P-value Q-test=0.4, Fixed effects OR (95% CI)=1.14 [0.88-1.48], Random effects OR (95% CI)=1.15 [0.88-1.49] in Cauc. in HWE; P-value Q-test=0.36, Fixed effects OR (95% CI)=1.45 [1.13-1.85], Random effects OR (95% CI)=1.44 [1.11-1.87] in East Asians; P-value Q-test=0.25, Fixed effects OR (95% CI)=1.19 [0.82-1.72], Random effects OR (95% CI)=1.19 [0.77-1.82] in Men; P-value Q-test=0.35, Fixed effects OR (95% CI)=1.70 [1.07-2.71], Random effects OR (95% CI)=1.71 [1.07-2.71] in Women; (TT + TC) vs. CC: P-value Q-test=0.2, Fixed effects OR (95% CI)=1.21 [1.00-1.25], Random effects OR (95% CI)=1.12 [0.98-1.29] in all; P-value Q-test=0.14, Fixed effects OR (95% CI)=1.12 [1.00-1.25], Random effects OR (95% CI)=1.12 [0.97-1.30] in All in HWE ; P-value Q-test=0.25, Fixed effects OR (95% CI)=1.19 [1.01-1.40] , Random effects OR (95% CI)=1.21 [0.98-1.48] in Caucasians; P-value Q-test=0.15, Fixed effects OR (95% CI)=1.19 [1.01-1.41], Random effects OR (95% CI)=1.23 [0.96-1.56] in Cauc. in HWE; P-value Q-test=0.16, Fixed effects OR (95% CI)=1.09 [0.91-1.30], Random effects OR (95% CI)=1.09 [0.86-1.39] in East Asians; P-value Q-test=0.26, Fixed effects OR (95% CI)=1.19 [0.93-1.53], Random effects OR (95% CI)=1.18 [0.89-1.58] in Men; P-value Q-test=0.12, Fixed effects OR (95% CI)=1.09 [0.85-1.41], Random effects OR (95% CI)=1.14 [0.75-1.74] in Women.	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 between the 10 studies; the FEs pooled OR was marginally significant. In subgroup analysis, there was moderate heterogeneity between the studies performed in Caucasians and in east Asians. The REs and FEs pooled ORs were not significant in Caucasians and in Asians. The genotype differences for the homozygotes revealed either absent or moderate heterogeneity and a significant association in the main analysis. In Caucasians, the association, however, was not significant whereas in east Asians the opposite pattern was detected. The recessive model for allele T produced the same pattern of genotypic association as found for the homozygote frequencies, and found no evidence for heterogeneity in Caucasians and in east Asians. The dominant model for the effect of Tallele in the main analysis and in Caucasians showed marginal (or no) association, and for the east Asians lack of significant association. The sensitivity analysis did not alter the pattern of results. Regarding sex, in female participants, there is indication of significant association for the difference in homozygotes (marginal) and the differences of genotypes supporting a recessive model.	Negative
MDD	MTHFR C677T	MTHFR	point mutation	T vs. C: P-value Q-test=0.19, Fixed effects OR (95% CI)=1.15 [0.97-1.36], Random effects OR (95% CI)=1.14 [0.92-1.41] in all; P-value Q-test=0.05, Fixed effects OR (95% CI)=1.02 [0.77-1.35], Random effects OR (95% CI)=1.04 [0.59-1.89] in Caucasians; P-value Q-test=0.55, Fixed effects OR (95% CI)=1.23 [1.00-1.52], Random effects OR (95% CI)=1.23 [1.00-1.52] in East Asians; TT vs. CC: P-value Q-test=0.41, Fixed effects OR (95% CI)=1.27 [0.86-1.84], Random effects OR (95% CI)=1.28 [0.88-1.86] in all; P-value Q-test=0.5, Fixed effects OR (95% CI)=1.04 [0.57-1.90], Random effects OR (95% CI)=1.05 [0.51-2.17] in Caucasians; P-value Q-test=0.17, Fixed effects OR (95% CI)=1.44 [0.90-2.31], Random effects OR (95% CI)=1.45 [0.90-2.33] in East Asians; TT vs. (TC + CC): P-value Q-test=0.68, Fixed effects OR (95% CI)=1.17 [0.83-1.65], Random effects OR (95% CI)=1.17 [0.83-1.66] in all; P-value Q-test=0.97, Fixed effects OR (95% CI)=0.97 [0.54-1.72], Random effects OR (95% CI)=0.97 [0.54-1.72] in Caucasians; P-value Q-test=0.21, Fixed effects OR (95% CI)=1.30 [0.84-2.01], Random effects OR (95% CI)=1.31 [0.85-2.02] in East Asians; (TT + TC) vs. CC: P-value Q-test=0.08, Fixed effects OR (95% CI)=1.21 [0.96-1.53], Random effects OR (95% CI)=1.20 [0.85-1.70] in all; P-value Q-test=0.04, Fixed effects OR (95% CI)=1.05 [0.72-1.53], Random effects OR (95% CI)=1.12 [0.41-3.08] in Caucasians; P-value Q-test=0.31, Fixed effects OR (95% CI)=1.32 [0.98-1.77], Random effects OR (95% CI)=1.32 [0.98-1.77] in East Asians	In depression, the pattern of results in terms of heterogeneity and association is similar to that of bipolar disorder, overall and in east Asians. In Caucasians, there was no association between C677T and depression. It seems that the MTHFR C677T polymorphism plays no role in the development of affective disorders.	Positive

Genes reported by this study for SZ/MDD

Disease	Gene	Description	Result Category
SZ	MTHFR	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.	Negative
MDD	MTHFR	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.	Positive