Gene Report

Basic information

Related studies

Functional annotation

Related other genetic factors

Overlap with SZ and MDD

ADD to My Gene Set

Comment on Gene

View All Comments on Gene

Basic Info

Approved Symbol	MTHFR
Approved Name	methylenetetrahydrofolate reductase (NAD(P)H)
Previous Name	5,10-methylenetetrahydrofolate reductase (NADPH)
Location	1p36.3
Position	chr1:11785723-11806920, -1
External Links	HGNC: 7436 Entrez Gene: 4524 Ensembl: ENSG00000177000 UCSC: uc001atc.2
No. of Studies	16 (Positive: 10; Negative: 6; trend: 0)
Overlap with SZ?	YES
Overlap with MDD?	YES

Gene related studies (count: 16)

Reference	Tested Markers	Statistical Values/Author Comments	Result Category	Comment on Study
Tan, E. C., 2004	Other variant: MTHFR_C677T	There was no significant difference in genotype distributions or allele frequencies of the MTHFR 667C>T polymorphism between controls and any of the diagnostic groups.	Negative	Comment on Study
Kunugi, H., 1998	Other variant: MTHFR_C677T	Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.	Negative	Comment on Study
Gilbody, S., 2007	Other variant: MTHFR_C677T	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 (I<sup>2</sup>= 42%)â€”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.	Positive	Comment on Study
El-Hadidy, M. A., 2013	Other variant: MTHFR_C677T	The present findings suggest that the MTHFR C677T polymorphism is likely associated with the risk of developing BD and schizophrenia, and influences the age at onset of schizophrenia but not the age at onset of BD.	Positive	Comment on Study
Arinami, T.,1997	Other variant: MTHFR_C677T	No significant differences were found in bipolar groups for MTHFR gene.	Negative	Comment on Study
Kempisty, B., 2007 (a)	Other variant: MTHFR_A1298C	The results confirm association of BD with the 1p36.3 MTHFR locus and with the methyl group transfer using folatedependent one-carbon pathway.	Positive	Comment on Study
Kempisty, B., 2006	Other variant: MTHFR_C677T	The data may suggest the association of homozygous 677TT genotype of MTHFR gene with bipolar disorder and schizophrenia.	Positive	Comment on Study
Zintzaras, E., 2006	Other variant: MTHFR_C677T	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	Comment on Study
Reif, A.,2005	Other variant: MTHFR_C677T, MTHFR_A1298C	The 1298C variant was significantly associated with both Bip and MD arguing that variation in the MTHFR gene contributes to the genetic risk for affective psychoses.	Positive	Comment on Study
Peerbooms, O. L.,2011	Other variant: MTHFR_A1298C	There was evidence for diagnostic moderation indicating a significant association with BPD	Positive	Comment on Study
Rai, V.,2011	Other variant: MTHFR_C677T	It shows meager association between MTHFR C677T genotype and bipolar disorder.	Positive	Comment on Study
Cohen-Woods, S.,2010	Other variant: MTHFR_C677T	Our findings suggest that the MTHFR C677T polymorphism is not involved in the genetic etiology of clinically significant BD.	Negative	Comment on Study
Yosifova, A.,2009	SNP: rs1801133	No SNP of this gene had significant association with BD in our population.	Negative	Comment on Study
Chen, Z.,2009	Other variant: MTHFR_C677T	In conclusion, pooled analysis of data from seven studies indicates MTHFR C677T is not significantly associated with bipolar disorder. Genome wide association studies also did not find any clues between markers of MTHFR gene and bipolar. Although MTHFR C677T is associated with schizophrenia by other metaanalysis, our data suggest no evidence for a major role of this polymorphism in the pathogenesis of bipolar disorder. The results implied different genetic background of schizophrenia and bipolar disorder to some extent.	Negative	Comment on Study
Wang, L. J., 2015	Other variant: MTHFR_C677T	Our findings support preliminary evidence that the COMT and MTHFR genes interact in BP-II, and they imply the connection of both dopaminergic pathways and methylation pathways in the pathogenesis of BP-II. Logistic regression analysis showed a significant interaction effect of the COMT Val158Met Val/Val genotype and the MTHFR C677T C/T + T/T genotype for the protective effect on the odds of developing BP-II.	Positive	Comment on Study
Hu C.Y., 2014	Other variant: MTHFR_exon 4_C677T, MTHFR_exon 7_A1298C	We conclude that MTHFR polymorphism is associated with BPD among Asian, African populations, but not the white.	Positive	Comment on Study

Gene functional annotation

Gene related GO terms (count: 27)

GO terms by PBA (count: 0)

GO terms by database search (count: 27)

ID	Name	Type	Evidence[PMID]	No. of Genes in BDgene
GO:0051593	response to folic acid	biological process	IEA	1
GO:0004489	methylenetetrahydrofolate reductase (NAD(P)H) activity	molecular function	IDA[12673793]; IGI[10551815]; IMP[12673793]; TAS	1
GO:0035999	tetrahydrofolate interconversion	biological process	IDA[12673793]; IEA; IGI[10551815]; IMP[12673793]	2
GO:0072341	modified amino acid binding	molecular function	IDA[20031578]	1
GO:0008015	blood circulation	biological process	TAS[7647779]	6
GO:0044281	small molecule metabolic process	biological process	TAS	117
GO:0005829	cytosol	cellular component	TAS	223
GO:0050667	homocysteine metabolic process	biological process	IDA[20031578]	1
GO:0009086	methionine biosynthetic process	biological process	IEA	3
GO:0042493	response to drug	biological process	IEA	57
GO:0046655	folic acid metabolic process	biological process	TAS	2
GO:0043005	neuron projection	cellular component	IEA	38
GO:0050661	NADP binding	molecular function	IEA	5
GO:0033274	response to vitamin B2	biological process	IEA	1
GO:0006766	vitamin metabolic process	biological process	TAS	5
GO:0032403	protein complex binding	molecular function	IPI[24769206]	16
GO:0006767	water-soluble vitamin metabolic process	biological process	TAS	5
GO:0006730	one-carbon metabolic process	biological process	IBA	2
GO:0050660	flavin adenine dinucleotide binding	molecular function	IDA[12673793]	5
GO:0070829	heterochromatin maintenance	biological process	IDA[24769206]	1
GO:0046500	S-adenosylmethionine metabolic process	biological process	IEA	1
GO:0055114	oxidation-reduction process	biological process	IEA	43
GO:0070555	response to interleukin-1	biological process	IEA	4
GO:0031060	regulation of histone methylation	biological process	IDA[24769206]	1
GO:0006555	methionine metabolic process	biological process	IGI[10551815]	2
GO:0001666	response to hypoxia	biological process	IEA	24
GO:0006520	cellular amino acid metabolic process	biological process	TAS[7647779]	5

Gene related KEGG pathways (count: 2)

KEGG pathways by PBA (count: 0)

KEGG pathways by database search (count: 2)

ID	Name	No. of Genes in BDgene	Brief Description
hsa00680	Methane metabolism	1
hsa00670	One carbon pool by folate	3

Gene related BioCarta pathways (count: 0)

Gene related interactors from protein-protein interactions data in HPRD (count: 0)

Related other genetic factors

Gene related SNPs (count: 1)

Literature-origin SNPs (count: 1)

rs_ID	Location	Functional Annotation	No. of Studies (Positive/Negative/Trend)
rs1801133	chr1:11796321 - 11796321(1)	downstream_gene_variant; missense_variant	1(0/1/0)

LD-proxies (count: 0)

Gene related CNVs (count: 0)

Gene related other variants (count: 4)

Variant Name	Variant Type	Location in Gene	No. of Studies (Positive/Negative/Trend)
MTHFR_exon 4_C677T	SNP	exon 4	1 (1/0/0)
MTHFR_exon 7_A1298C	SNP	exon 7	1 (1/0/0)
MTHFR_C677T	point mutation		13 (5/8/0)
MTHFR_A1298C	point mutation		4 (3/1/0)

Gene related regions (count: 5)

Region Name	Position	No. of Studies (Positive/Negative/Trend)
1p35-p36	chr1:0-34300000	1 (1/0/0)
1p33-p36	chr1:0-50200000	1 (0/0/1)
1p36.22	chr1:9100000-12500000	1 (0/0/1)
1p36	chr1:0-27600000	1 (0/1/0)
Chr 1	chr1:0-248956422	2 (0/2/0)

Overlap with schizophrenia (SZ) and major depressive disorder (MDD)

Gene relationship with SZ

Overlap with SZ from cross-disorder studies (count: 10)

Reference	Description	Result Category
15564899	There was no significant difference in genotype distributions or allele frequencies of the MTHFR 667C>T polymorphism between controls and any of the diagnostic groups.	Negative
9342205	The genotype homozygous for the T677 allele was significantly frequently observed in schizophrenics with an odds ratio of 1.9 (P = 0.0006), and in patients with major depression with an odds ratio of 2.8 (P = 0.005). Our data suggest associations of the MTHFR gene variant with schizophrenia and depression in the Japanese.	Positive
16691128	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
24938371	We conclude that MTHFR polymorphism is associated with SZ among Asian, African populations, but not the white.	Positive
21185933	MTHFR was not significantly associated with SZ in our study.	Negative
16545905	The data may suggest the association of homozygous 677TT genotype of MTHFR gene with bipolar disorder and schizophrenia.	Positive
9774778	Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.	Negative
17188847	The results confirm association of schizophrenia with the 1p36.3 MTHFR locus and with the methyl group transfer using folatedependent one-carbon pathway.	Positive
17074966	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 (I<sup>2</sup>= 42%)â€”based on 2, 762 cases and 3, 363 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.	Positive
24276736	The present findings suggest that the MTHFR C677T polymorphism is likely associated with the risk of developing BD and schizophrenia, and influences the age at onset of schizophrenia but not the age at onset of BD.	Positive

Overlap with SZ from candidate gene intersection analysis (count: 23)

Reference	ID in SZGene	Result Category
15564899	4	Negative
9342205	4	Positive
15806605	4	Positive
19564051	4	Positive
15289817	4	Negative
17503473	4	Negative
20694488	4	Positive
16076517	4	Negative
16545905	4	Positive
19158809	4	Negative
16084002	4	Positive
10208443	4	Positive
9774778	4	Negative
16969279	4	Negative
20044984	4	Positive
14499487	4	Positive
19939410	4	Negative
18165967	4	Negative
18988738	4	Positive
10889537	4	Positive
17188847	4	Positive
20421849	4	Negative
16641680	4	Positive

Gene relationship with MDD

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

Reference	Description	Category in MDD
15564899	There was no significant difference in genotype distributions or allele frequencies of the MTHFR 667C>T polymorphism between controls and any of the diagnostic groups.	Negative
9342205	The genotype homozygous for the T677 allele was significantly frequently observed in schizophrenics with an odds ratio of 1.9 (P = 0.0006), and in patients with major depression with an odds ratio of 2.8 (P = 0.005). Our data suggest associations of the MTHFR gene variant with schizophrenia and depression in the Japanese.	Positive
16691128	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
17074966	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 (I<sup>2</sup>= 0%)â€”based on 1, 280 cases and 10, 429 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.	Positive
16055253	The 1298C variant was significantly associated with both Bip and MD arguing that variation in the MTHFR gene contributes to the genetic risk for affective psychoses.	Positive
9774778	Our results suggest that homozygosity for the T677 allele of the MTHFR gene is unlikely to play a major role in the pathogenesis of schizophrenia or affective disorders in our sample.	Negative

Overlap with MDD from candidate gene intersection analysis (count: 2)

Reference	Description	Category in MDD	Link in MK4MDD
18165972	no significant differences in genotype or allele frequencies between depressive patients and controls were observed.	Neg	MTHFR
23255668	We found no significant association of either the BDNF G196A or MTHFR C677T polymorphisms with major depressive disorder neither in female nor male group of patients.	Neg	MTHFR

View in gBrowse

Region: chr1:11785723..11806920 View in gBrowse