C677T methylenetetrahydrofolate reductase gene polymorphisms in bipolar disorder: an association study in the Chinese population and a meta-analysis of genetic association studies.
ABSTRACT The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T is suspected to be a risk factor for psychiatric disorders, but it remains uncertain whether the MTHFR C677T variant is associated with bipolar disorders. To investigate possible association, unrelated controls (n=461) with no history of psychiatric disorders and patients (n=501) diagnosed with bipolar disorder were recruited in this study. In addition, six association studies published up to June 2008 were included in a subsequent meta-analysis. No significant difference was found in either allele frequencies or genotype distribution between patients and controls in our association study in the Chinese population. Similarly, the meta-analysis result showed no significant association between MTHFR C677T and bipolar disorder. In conclusion, the MTHFR C677T variant is unlikely to play a major role in the susceptibility to bipolar disorder, although MTHFR plays an important role in the one-carbon metabolism and DNA methylation.
Article: Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope.[show abstract] [hide abstract]
ABSTRACT: No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.American Journal of PharmacoGenomics 02/2005; 5(3):149-60.
[show abstract] [hide abstract]
ABSTRACT: Juvenile bipolar disorder (JBD) has been a subject of significant research and debate. Phenotypic differences between JBD and adult-onset bipolar disorder have led researchers to question whether or not similar neuropathologic mechanisms will be found. While much is known about the genetic and environmental contributions to the adult-onset phenotype, less is known about their contributions to JBD. Here, we review family, twin, adoption, and molecular genetic studies of JBD. Behavioral genetic data suggest both genetic and environmental contributions to JBD, while molecular genetic studies find linkage to age of onset of bipolar disorder to chromosomes 12p, 14q, and 15q. Additionally, changes associated with symptom age of onset have been recently reported in the brain-derived neurotrophic factor (BDNF) and glycogen synthase kinase 3-beta (GSK3-beta) genes. We contend that further progress in discovering the precise genetic and environmental contributions to JBD may depend on advances in phenotypic refinement, an increased appreciation of comorbid conditions, and more investigation of the longitudinal course of the disorder.Bipolar Disorders 01/2006; 7(6):598-609. · 5.29 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Bipolar disorder is a highly recurrent and chronic psychiatric condition that shortens life expectancy, causes functional impairment and disruption to social, work and family life. Several forms of bipolar disorder are recognised, including both bipolar I and bipolar II disorder. Bipolar I is characterised by recurrent episodes of depression and mania whereas bipolar II disorder is characterised by recurrent depression and hypomania, a milder form of mania. There has been debate concerning the definition of hypomania since at least the 1970s. The main areas of argument focus on the minimum duration of hypomania, its stem criteria and the number of symptoms required for diagnosis. Arriving at the correct definition of hypomania is a key diagnostic issue. There is increasing evidence for the existence of a broad spectrum of bipolar disorders, and data demonstrating the clinical validity of modifying some of the criteria for hypomania are reviewed here.European Neuropsychopharmacology 09/2003; 13 Suppl 2:S43-50. · 4.05 Impact Factor
Neuroscience Letters 449 (2009) 48–51
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/neulet
C677T methylenetetrahydrofolate reductase gene polymorphisms in bipolar
disorder: An association study in the Chinese population and a meta-analysis
of genetic association studies
Zhuo Chena, Yun Liua, Di Zhanga, Zhe Liua, Peng Wangc, Daizhan Zhoua, Teng Zhaoa,
Ting Wanga, He Xua,b, Sheng Lia,b, Guoyin Fengd, Lin Hea,b,e,∗, Lan Yua,b,∗
aInstitute for Nutritional Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Tai Yuan Road, Shanghai 200031, China
bBio-X Center, Shanghai Jiao Tong University, Hao Ran Building, 1954 Hua Shan Road, Shanghai 200030, China
cThe Fourth People’s Hospital of Wuhu, Wuhu, Anhui Province, China
dShanghai Institute of Mental Health, Shanghai, China
eInstitutes of Biomedical Sciences, Fudan University, Shanghai, China
a r t i c l ei n f o
Received 26 August 2008
Received in revised form 14 October 2008
Accepted 21 October 2008
a b s t r a c t
The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T is suspected to be a risk factor
for psychiatric disorders, but it remains uncertain whether the MTHFR C677T variant is associated with
bipolar disorders. To investigate possible association, unrelated controls (n=461) with no history of psy-
chiatric disorders and patients (n=501) diagnosed with bipolar disorder were recruited in this study. In
addition, six association studies published up to June 2008 were included in a subsequent meta-analysis.
No significant difference was found in either allele frequencies or genotype distribution between patients
no significant association between MTHFR C677T and bipolar disorder. In conclusion, the MTHFR C677T
variant is unlikely to play a major role in the susceptibility to bipolar disorder, although MTHFR plays an
important role in the one-carbon metabolism and DNA methylation.
© 2008 Elsevier Ireland Ltd. All rights reserved.
Bipolar disorder is a common but severe mental illness associated
with considerable morbidity and mortality , and the prevalence
over a life time is approximately 1% or slightly higher in the general
population [5,25]. Several forms of bipolar disorder are recognized,
including bipolar disorder l (BD-l) and bipolar disorder ll (BD-
ll). Evidences from family, twin and adoption studies revealed a
strong genetic contribution to bipolar disorders in both juveniles
and adults [3,27]. Association studies have identified several sus-
pect chromosome loci and candidate genes, but none has been
Methylenetetrahydrofolate reductase (MTHFR) plays a central
role in folate-mediated one-carbon transfer reactions. It catalyzes
10-methylenetetrahydrofolate to 5- methylenetetrahydrofolate,
the active form of folate required for methylation of homocysteine
versal methyl donor for several biological methylation reactions.
∗Corresponding author at: Institute for Nutritional Science, Institutes for Biolog-
ical Sciences, Chinese Academy of Sciences, Tai Yuan Road, Shanghai 200031, China.
Tel.: +86 21 54920227; Fax: +86 21 54920227.
E-mail addresses: email@example.com (L. He), firstname.lastname@example.org (L. Yu).
Deficient activity of MTHFR may be associated with psychiatric
conditions such as schizophrenia  and affective disorders .
C677T is a common single nucleotide polymorphism (SNP) in
MTHFR, leading to a substitution of alanine with valine. This func-
tional mutation results in diminished enzyme activity, with the TT
homozygote variants having only 30% and the TC heterozygotes
65% enzyme activity compared to the CC wild type . The low
enzyme activity of MTHFR may lead to sever consequences, par-
ticularly increased homocysteine level in the blood and altered
methylation status. High levels of homocysteine may be toxic to
dopaminergic neurons  and dysfunction of dopamine neurons
has been implicated in bipolar disorders .
sible links between the MTHFR C677T polymorphism and various
psychiatric disorders but no consistent results have been obtained
with regard to either schizophrenia or bipolar disorder. Although
some studies [18,20,29] suggest that MTHFR C677T is associated
tigate the role of MTHFR C677T in bipolar disorder, we conducted
an association study in the Chinese population. In addition, we per-
formed a meta-analysis including our study, to provide an overall
estimation of association.
0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved.
Z. Chen et al. / Neuroscience Letters 449 (2009) 48–51
Genotype distribution and allele frequencies for MTHFR C677T polymorphism among bipolar disorder patients and controls.
Genotype distribution (number/ V frequency)Allele (number/frequency) SignificanceOdds ratio (95% CI)
Control46173(0.158)235(0.510)153(0.332) 922381(0.413) 541(0.587)
BD total50192(0.184)231(0.461) 178(0.355)1002415(0.414)587(0.586)
0.9014 (0.6905, 1.1768)a
1.1956 (0.8534, 1.6749)b
BD-I 41977(0.184) 194(0.463) 148(0.353)838348(0.415) 490(0.585)
0.9096 (0.6883, 1.2020)a
1.1967 (0.8419, 1.7009)b
BD-II82 15(0.183)37(0.451) 30(0.366)164 67(0.409)97(0.591)
0.8610 (0.5278, 1.4046)a
1.1899 (0.6445, 2.1969)b
aThe odds ratio was calculated for patients with T allele (CT+TT vs. CC genotype).
bThe odds ratio was calculated for patients homozygous for T allele (TT vs. CT+CC genotype).
Our study was approved by the ethics committee of the Shang-
hai Institute for Biological Sciences, Chinese Academy of Sciences.
Informed consent was obtained from each participant of 501 unre-
lated patients with bipolar disorder (419 BD-land 82 BD-ll) and
461 healthy individuals from Anhui Province of China. Consensus
diagnoses were made for each patient by at least two experienced
psychiatrists according to DSM-lV criteria. Patients and controls
were well matched (average age of controls, 36.6±7.2; average age
of cases, 37.8±12.7).
Peripheral blood was collected from each individual and
genomic DNA was extracted according to standard procedures.
MTHFR C677T polymorphisms were detected by direct DNA
sequencing, using a BigDye Terminator Cycle Sequencing Kit and
an ABI PRISM 3100 DNA sequencer (PE Applied Biosystems, Perkin-
Elmer). Polymerase chain reaction (PCR) was performed for the
specific region of the MTHFR gene and consisted of an initial denat-
30s at 72◦C, followed by a terminal extension at 72◦C for 10min.
PCR primers were as follow: forward primer: 5?GGAAGGTGCAAGA-
TCAGAGC3?; reverse primer: 5?CTGGGAAGAACT CAGCGAAC3?. We
resequenced 32 random selected samples and it reported 100%
concordance in genotyping.
The genotype distribution in all groups was tested for deviation
distribution and allele frequencies were conducted online by Shi
and He .
All studies up to September 2008 investigating an association
between MTHFR C677T polymorphism and bipolar disorder were
searched from PubMed database with key words ‘MTHFR’ and
‘bipolar’. Reference lists were carefully examined for relevant stud-
and our own association study in the Chinese population which
presented independent and sufficient data to calculate the OR with
CI and P-value were recruited. All seven were case-control stud-
ies dealing with either East Asians or Caucasians, including 1260
patients and 1911 controls.
two tables in which subjects were classified by diagnostic category
and type of allele (T versus C). From each table, an odds ratio and
sampling variances were calculated. Cochran’s ?2-based Q statistic
test was performed to assess possible heterogeneity in the indi-
vidual studies. The significance of the overall OR was determined
by the Z-test using fixed effects and random effects models. On a
condition that heterogeneity was found, the random effects model,
which yields wider confidence intervals (CIs), was adopted; oth-
erwise, both the fixed and random effects model can be adopted.
The sensitivity analysis was conducted, to ensure that no individ-
ual study was entirely responsible for the combined results and
the Egger’s test for funnel plot asymmetry was applied to check for
publication bias. All the analysis was conducted on Comprehensive
Meta Analysis software (Version 1.0.23, BIOSTAT, Englewood, NJ,
USA) and type I error rate was set at 0.05, P-values two-tailed.
Genotype distributions were in Hardy–Weinberg equilib-
rium for patients (total patients, ?2=1.2449, P=0.2645; BD-l,
?2=0.9103, P=0.3401; BD-ll, ?2=0.3606, P=0.5482) and controls
(?2=1.2075, P=0.2719). Differences in genotype distribution and
allele frequencies were conducted online by Shi and He . There
was no significant difference between patients and controls under
either dominant model or recessive model level in the Chinese
population. (Table 1)
Meta-analysis was conducted in East Asians, Caucasians and all
the populations, respectively. There are no heterogeneity between
East Asians (P-value(Q-test)=0.357, I2=7.202%), so both fixed effect
model and random effect model were used. Differently, the het-
erogeneity between Caucasians and all the populations are quite
high, (P-value(Q-test)=0.000, I2=88.5% for Caucasians; P-value
(Q-test)=0.002, I2=71.2% for overall), therefore the random effect
model was used. As Table 2 shows, there was no significant asso-
ciation between MTHFR C677T and bipolar disorder in East Asians,
Caucasians or all of them.
Sensitivity analysis indicated the meta-analysis results for
were excluded. Egger’s Test showed no publication bias.
To summarize, the results of our association study suggested
MTHFR C677T is not a major risk factor for bipolar disorder, which
sible that some factors may influence the detection of the potential
association of MTHFR C677T and bipolar disorder.
Firstly, folate and homocysteine levels were not adjusted in
these association studies because of not having data. Low folate
ders [9,23]. Previous investigations have shown that MTHFR TT677
homozygous subjects suffer more from high serum homocysteine
levels, the indicator of altered one-carbon metabolism, under low
serum folate conditions [12,16]. However, there is no C677T geno-
typic difference of total plasma homocysteine concerntration in
those subject with higher folate levels , indicating high level
of folate have a compensation effect on reduced enzyme activity of
MTHFR. Thus, folate and homocysteine levels should be considered
if further association studies between MTHFR and bipolar disorder
Secondly, potential interaction between MTHFR and other genes
involved in folate-mediated one-carbon transfer reactions, such
as methylenetetrahydrofolate dehydrogenase and methionine syn-
thase which showed associations with bipolar disorder , may
reduce the possibility of detecting their individual effects through
association studies. Future studies may be able to detect and
characterize interactions among the loci in these genes using
Z. Chen et al. / Neuroscience Letters 449 (2009) 48–51
Meta-analysis of case-control studies between MTHFR C677T polymorphism and bipolar disorder.
Genotype distribution (frequencies)
0.991 (0.617, 1.592)
1.349 (1.007, 1.808)
1.210 (0.804, 1.820)
0.783 (0.532, 1.152)
1.898 (1.397, 2.577)
0.826 (0.578, 1.180)
1.004 (0.837, 1.204)
1.094 (0.953, 1.256)b
1.101 (0.949, 1.277)c
1.080 (0.596, 1.954)d
1.116 (0.889, 1.401)e
aChen is regarded as our association study in the Chinese population.
bWas calculated under fixed effect model while.
c,d,eWere calculated under random effect model.
statistical methods such as multifactor dimensionality reduction
Furthermore, bipolar disorder is a complex disease resulting
such as DNA methylation also play a role in bipolar disorders [2,30]
and the MTHFR C677T polymorphism has been found to affect DNA
could do little to solve these problems. Thus, more genetic and
epigenetic well designed studies are needed to verify the effect of
MTHFR on bipolar disorder.
Besides, association between MTHFR C677T bipolar disorder l
and bipolar disorder ll were not analyzed in the meta-analysis
because of having no detailed information. However, bipolar disor-
whereas bipolar disorder ll disorder is characterized by recurrent
depression and hypomania, a milder form of mania . These two
types are not identical and MTHFR C677T may have different distri-
bution with them.
We also noticed that high heterogeneity existed in Caucasians
and meta-analysis in such condition may not reflect the truth.
Therefore, whether MTHFR C677T is associated with bipolar disor-
der in Caucasians are not clear unless more studies are performed.
In conclusion, pooled analysis of data from seven studies indi-
cates 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 [1,8]. Although
MTHFR C677T is associated with schizophrenia by other meta-
analysis, 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.
We are deeply grateful to all bipolar disorder patients and
healthy controls participating in the studies, as well as to the psy-
chiatrists for their help in the recruitment and identity of bipolar
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