BDgene

Core Gene from Gene Prioritization Pathways from PBA (Pathway-based Analysis) Enriched Pathways for Core Genes Enriched Pathways for Cross-disorder Genes

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Basic Info

Name	MTHFR C677T
Type	point mutation
Related Gene	MTHFR
No. of Study	13 (Positive: 5; Negative 8; Trend: 0)
Overlap with SZ?	YES
Overlap with MDD?	YES

Variant related studies (count: 13)

Reference	Allele Change	Risk Allele	Statistical Values	Author Comments	Result Category
Tan, E. C., 2004	C>T		genotypic P-value = 0.230, X²=2.944, allelic P-value = 0.441, X²=0.594 in females with bipolar; genotypic P-value = 0.820, X²=0.398, allelic P-value = 0.546, X²=0.365 in males with bipolar; genotypic P-value = 0.104, X²=4.519, allelic P-value = 0.301, X²=1.069 in all female patients with bipolar; genotypic P-value = 0.700, X²=0.715, allelic P-value = 0.431, X²=0.619 in all male patients with bipolar. X²==3.119, d.f.=1, P=0.077, OR=1.46, 95% confidence interval=0.96-2.22 between controls and all psychiatric cases combined in the dominant model.	For bipolar disorder, there was also no difference for both ..... More For bipolar disorder, there was also no difference for both genotype and allele frequencies. The level of significance as measured by the P value did not improve even when data was stratified according to gender. When patients from all the three diagnostic group were combined and analyzed against the controls, there was no significant difference in terms of genotype and allele frequencies for males. With the female group, there was improvement in the level of significance for difference in genotype distribution between controls and all patients. In the dominant model, there was marginally significant difference between controls and and all psychiatric cases combined. Less	Negative
Arinami, T.,1997	C677T		Chi-square tests:P > 0.05,OR(95%CI) = 1.0 (0.5â€“2.8)	No significant differences were found in bipolar groups.	Negative
Zintzaras, E., 2006	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 ..... More 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. Less	Positive
Kempisty, B., 2006	C/T		P-value = 0.0003, OR (95% CI)=1.988 (1.370-2.883) for bipolar I patients with 677CT or 677TT genotypes; P-value = 0.0071, OR (95% CI)=2.758 (1.283-5.931) among 677TT homozygous patients; P-value = 0.0784, OR (95% CI)=1.62 (0.945-2.776 for 677T allele in the female patients; P-value = 0.0008, OR (95% CI)=2.393 (1.429-4.006) for 677T allele in the male patients	The frequency of the T allele was 1.7-fold times higher in t..... More The frequency of the T allele was 1.7-fold times higher in the whole group of bipolar patients as compared to the controls and was 28% and 17% in those groups, respectively. The frequencies of homozygous 677TT genotype in patients and controls reached 10% and 4%, respectively. Although the frequency of heterozygous 677CT patients was higher than in controls, we did not observe significant differences. The stratification of patients based on gender revealed association of 677T allele with bipolar disorder type I in the male patients. Less	Positive
Chen, Z.,2009	T/C		chi-square test and odds ratio test:1.calculated for patients with T allele (CT + TT vs. CC genotype).BD total: X²=0.5826, P-value = 0.4453, Odds ratio (95% CI):0.9014 (0.6905, 1.1768); BD-l, X²=0.4439, P-value = 0.5052, Odds ratio (95% CI):(0.6883, 1.2020); BD-ll, X²=0.3595 , P-value = 0.5488, Odds ratio (95% CI):0.8610 (0.5278, 1.4046). 2.calculated for patients homozygous for T allele (TT vs. CT + CC genotype).BD total: X²=1.0799 , P-value = 0.2987, Odds ratio (95% CI):1.1956 (0.8534, 1.6749); BD-l, X²=1.0030, P-value = 0.3166, Odds ratio (95% CI):1.1967 (0.8419, 1.7009); BD-ll, X²=0.3096, P-value = 0.5779, Odds ratio (95% CI):1.1899 (0.6445, 2.1969).	There was no significant difference between patients and con..... More There was no significant difference between patients and controls under either dominant model or recessive model level in the Chinese population. Less	Negative
Rai, V.,2011	C677T		Meta analysis:The fixed effect pooled OR was 1.07 (95% CI; 0.98 to 1.17) and Cochran Q was 24.13 (df = 7; p=0.0011). The random effect pooled OR was 1.07(95% CI; 0.87 to 1.32) and Cochran Q was 24.13 (df = 7; p=0.0011).	The study was significant and shows meager association betwe..... More The study was significant and shows meager association between MTHFR C677T genotype and bipolar disorder. Less	Positive
Wang, L. J., 2015	G/T		allelic P-value=0.13, X²=2.3; genotypic P-value=0.16, X²=3.61	For MTHFR C677T, neither the genotypes nor the allelic distr..... More For MTHFR C677T, neither the genotypes nor the allelic distribution were associated with the risk of BP-II. Less	Negative
Reif, A.,2005	C677T		X² test:for Bip, X²=2.29, genotype P-value = 0.319	No significant associations were found.	Negative
Jonsson, E. G., 2008			Controls versus bipolar in Norway group, genotype distribution, X²=1.30 (df=2), P value=0.52, allele distribution, X²=1.10, (df=2), P value=0.29.	There were no statistically significant allele or genotype c..... More There were no statistically significant allele or genotype case-control differences. Less	Negative
El-Hadidy, M. A., 2013	C/T		allelic P-value=0.112 for allele C, X²=2.52, OR (CI)=1.871 (0.85-4.09), P-value=0.001 for allele T, X²=11.528, OR (CI)=0.438 (0.27-0.71); genotypic P-value=0.005 for CC, X²=8.039, OR (CI)=2.286 (1.29-4.07)P-value=0.015 for CT, X²=5.967, OR (CI)=0.481 (0.27-0.87), P-value=0.362 for TT, X²=0.830, OR (CI)=0.603 (0.20-1.81)	There is a significant increase in CC genotype distribution ..... More There is a significant increase in CC genotype distribution in the control group when compared with the BD and schizophrenia groups. The CT genotype distribution is significantly increased in the BD group versus the control group. The T allele is significantly prevalent in the BD and schizophrenia groups compared with the control group. Less	Positive
Cohen-Woods, S.,2010	C/T		Association analysis:Genotype distribution CC versus CT versus TT: X²=2.37, df=2, P-value = 0.31.Genotype distribution CC versus CT/TT: X²=0.96, df=1, P-value = 0.96; odds ratio=0.92 (0.78-1.09).Genotype distribution CC versus TT: X²=2.36, df=1, P-value = 0.12; odds ratio=0.81 (0.62-1.06).Allele distribution C versus T: X²=2.01, df=1, Cochran-Armitage P-value = 0.16; common odds ratio=0.9.	No significant association was observed in BD.	Negative
Kunugi, H., 1998			chi-square P-value=0.09, X²=2.9, OR=1.6 (0.93-2.78)	there was no significantly increased frequency of homozygosi..... More there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls. Less	Negative
Gilbody, S., 2007	C>T		Fixed-effects OR_TTvCC = 1.82, 95 percent CI: 1.22, 2.70; I² = 42 percent. Fixed-effects OR_TvC = 1.41, 95 percent CI: 1.19, 1.68; I² = 54 percent.	There was an increased risk of bipolar disorder associated w..... More There was an increased risk of bipolar disorder associated with the homozygote variant genotype. The frequency of the T allele was increased among persons with bipolar disorder. Less	Positive

Overlap with SZ from cross-disorder studies (count: 8)

Reference	Statistical Result	Description	Result Category
El-Hadidy, M. A., 2013	allelic P-value<0.05 for allele C, X²=22.171, OR (CI)=4.677 (2.36-9.28), P-value<0.05 for allele T, X²=14.42, OR (CI)=0.412 (0.26-0.65); genotypic P-value=0.016 for CC, X²=5.829, OR (CI)=2.00 (1.14-3.52), P-value=0.826 for CT, X²=0.048, OR (CI)=0.934 (0.51-1.72), P-value=0.001 for TT, X²=10.667, OR (CI)=0.224 (0.09-0.58)	There is a significant increase in CC genotype distribution in the control group when compared with the BD and schizophrenia groups. The TT genotype distribution is significantly increased in the schizophrenia group versus the control group. The T allele is significantly prevalent in the BD and schizophrenia groups compared with the control group. The C allele is prevalent in the control group and its prevalence is statistically significant only when compared with the schizophrenia group.	Positive
Zintzaras, E., 2006	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
Kempisty, B., 2006	P-value = 0.002, OR (95% CI)=1.796 (1.237-2.609) for patients with schizophrenia and with 677CT or 677TT genotypes; P-value = 0.0071, OR (95% CI)=2.758 (1.283-5.931) among 677TT homozygous patients; P-value = 0.0955, OR (95% CI)=1.572 (0.922-2.679) for 677T allele in the female patients; P-value = 0.0073, OR (95% CI)=2.036 (1.207-3.433) for 677T allele in the male patients	We observed 1.5-fold times higher distribution of T677 allele in patients with schizophrenia as compared to controls. The frequency of T677 allele in patients with schizophrenia was 26%. The distribution of homozygous 677TT genotype was 2.5 times higher in patients with schizophrenia than in controls. Although the frequency of heterozygous 677CT genotype was higher in patients as compared to controls, it did not exhibit significant differences. Gender classification of patients indicated significant association of 677T allele with schizophrenia in the male patients.	Positive
Kunugi, H., 1998	chi-square P-value=0.38, X²=0.28, OR=1.2 (0.77-1.96)	there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls.	Negative
Gilbody, S., 2007	Fixed-effects OR_TTvCC = 1.44, 95 percent CI: 1.21, 1.70; I² = 42 percent. Fixed-effects OR_CTvCC = 1.07, 95 percent CI: 0.96, 1.20; I² = 41 percent.	There was an increased risk of schizophrenia among homozygote variants (TT), with low statistical between-study heterogeneity. A nonsignificant association was observed for heterozygotes.	Positive
Tan, E. C., 2004	genotypic P-value = 0.268, X²=2.636, allelic P-value = 0.345, X²=0.893 in females with schizophrenia; genotypic P-value = 0.731, X²=0.628, allelic P-value = 0.509, X²=0.437 in males with schizophrenia; genotypic P-value = 0.104, X²=4.519, allelic P-value = 0.301, X²=1.069 in all female patients with schizophrenia; genotypic P-value = 0.700, X²=0.715, allelic P-value = 0.431, X²=0.619 in all males patients with schizophrenia; X²=2.724, d.f.=1, P-value = 0.099, OR=1.47 95% confidence interval=0.93-2.33 between controls and patients with schizophrenia; X²==3.119, d.f.=1, P=0.077, OR=1.46, 95% confidence interval=0.96-2.22 between controls and all psychiatric cases combined in the dominant model	Genotype and allele frequencies between controls and patients with schizophrenia were similar. When subjects were stratified according to gender, the difference in terms of P value remained insignificant for both males and females. When patients from all the three diagnostic group were combined and analyzed against the controls, there was no significant difference in terms of genotype and allele frequencies for males. With the female group, there was improvement in the level of significance for difference in genotype distribution between controls and all patients. In the dominant model, there was marginally significant difference between controls and patients with schizophrenia and and all psychiatric cases combined.	Negative
Arinami, T.,1997	Chi-square tests:P < 0.006,OR(95%CI) = 1.9 (1.3â€“2.9)	Significant differences were found in SZ groups.	Positive
Jonsson, E. G., 2008	Controls versus schizophrenia in Denmark group, genotype distribution, X²=0.19 (df=2), P value=0.91, allele distribution, X²=0.17, (df=2), P value=0.68. Controls versus schizoaffective in Denmark group, genotype distribution, X²=2.16 (df=1), P value=0.34, allele distribution, X²=0.70, (df=1), P value=0.34.	There were no statistically significant allele or genotype case-control differences.	Negative

Overlap with MDD from cross-disorder studies (count: 6)

Reference	Statistical Result	Description	Result Category
Zintzaras, E., 2006	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
Kunugi, H., 1998	chi-square P-value=0.84, X²=0, OR=1.1 (0.51-2.31)	there was no significantly increased frequency of homozygosity for the T677 allele in any of the diagnostic groups, compared to the controls.	Negative
Reif, A.,2005	X² test:for MD, X²=1.09, genotype P-value = 0.580	No significant associations were found.	Negative
Gilbody, S., 2007	Fixed-effects OR_TTvCC = 1.36, 95 percent CI: 1.11, 1.67; I² = 0 percent. Fixed-effects OR_CTvCC = 1.10, 95 percent CI: 0.96, 1.25; I² = 49 percent.	There was an increased risk of depression among persons with the homozygote variant TT genotype, with no discernible statistical between-study heterogeneity. We found a smaller magnitude of association for heterozygotes that was of borderline significance and subject to greater between-study heterogeneity.	Positive
Tan, E. C., 2004	genotypic P-value = 0.111, X²=4.406, allelic P-value = 0.345, X²=0.893 in females with unipolar; genotypic P-value = 0.545, X²=1.216, allelic P-value = 0.308, X²=1.038 in males with unipolar; genotypic P-value = 0.104, X²=4.519, allelic P-value = 0.301, X²=1.069 in all female patients with unipolar; genotypic P-value = 0.700, X²=0.715, allelic P-value = 0.431, X²=0.619 in all males patients with unipolar. X²==3.119, d.f.=1, P=0.077, OR=1.46, 95% confidence interval=0.96-2.22 between controls and all psychiatric cases combined in the dominant model.	The difference between control and unipolar depressive patients was not significant at the genotype level or the allelic level. When the data were analyzed separately for each gender, only the female group showed improved statistical significance for genotype distribution. When patients from all the three diagnostic group were combined and analyzed against the controls, there was no significant difference in terms of genotype and allele frequencies for males. With the female group, there was improvement in the level of significance for difference in genotype distribution between controls and all patients. In the dominant model, there was marginally significant difference between controls and and all psychiatric cases combined.	Negative
Arinami, T.,1997	Chi-square tests:P < 0.006,OR(95%CI) = 2.8 (1.3â€“6.4)	There was a significant difference between patients with unipolar disorder and controls.	Positive