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.

Full text

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Neuroscience Letters 449 (2009) 48–51
Contents lists available at ScienceDirect
Neuroscience Letters
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
Article history:
Received 26 August 2008
Received in revised form 14 October 2008
Accepted 21 October 2008
Keywords:
MTHFR
Bipolar
Methylation
Folate
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
andcontrolsinourassociationstudyintheChinesepopulation.Similarly,themeta-analysisresultshowed
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 [7], 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
substantiated.
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
tomethionine,whichcanconverttoS-adenosymethionion,theuni-
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: helin@bio-x.cn (L. He), lyu01@sibs.ac.cn (L. Yu).
Deficient activity of MTHFR may be associated with psychiatric
conditions such as schizophrenia [11] and affective disorders [24].
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 [13]. 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 [21] and dysfunction of dopamine neurons
has been implicated in bipolar disorders [14].
AnumberofassociationstudiesonMTHFR,havefocusedonpos-
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
withbipolardisorder,someothers[6,17,22]donot.Tofurtherinves-
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.
doi:10.1016/j.neulet.2008.10.077

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Z. Chen et al. / Neuroscience Letters 449 (2009) 48–51
49
Table 1
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)
n
TTTCCC
n
TC
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)
?2=0.5826 P=0.4453
?2=1.0799 P=0.2987
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)
?2=0.4439 P=0.5052
?2=1.0030 P=0.3166
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)
?2=0.3595 P=0.5488
?2=0.3096 P=0.5779
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-
urationat95◦Cfor4min,35cyclesof30sat94◦C,40sat62◦C,and
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
fromHardy–Weinbergequilibrium(HWE).Differencesingenotype
distribution and allele frequencies were conducted online by Shi
and He [26].
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-
ies.Sixpublishedinpeer-reviewedjournalpapers[6,17,18,20,22,29]
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.
Datafromthecase-controlstudiesweresummarizedintwo-by-
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 [26]. 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
MTHFRC677Twererobustanddidnotalterwhenindividualstudies
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
isquiteconsistentwiththemeta-analysisresult.However,itispos-
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
andhighhomocysteinelevelsarerelatedtoneuropsychiatricdisor-
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 [10], 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
are conducted.
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 [19], 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

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Z. Chen et al. / Neuroscience Letters 449 (2009) 48–51
Table 2
Meta-analysis of case-control studies between MTHFR C677T polymorphism and bipolar disorder.
First
author
Racial
descent
Number
(bipolar/control)
Genotype distribution (frequencies)
Hardy–Weinberg P-value
for control
Odds ratio
TT
TC
CC
(95% CI)
Bipolar
Control
Bipolar
Control
Bipolar
Control
Arinami
Japan
40/419
5(0.125)
51(0.122)
20(0.500)
214(0.511)
15(0.375)
154(0.368)
0.43
0.991 (0.617, 1.592)
Kunugi
Japan
143/258
28(0.196)
34(0.132)
74(0.517)
129(0.500)
41(0.287)
95(0.368)
0.10
1.349 (1.007, 1.808)
Tan
China
167/120
8(0.048)
7(0.058)
60(0.359)
33(0.275)
99(0.953)
80(0.667)
0.25
1.210 (0.804, 1.820)
Reif
German
92/176
10(0.109)
21(0.119)
34(0.370)
80(0.455)
48((0.522)
75(0.426)
0.96
0.783 (0.532, 1.152)
Kempisty
Poland
200/300
19(0.095)
11(0.037)
73(0.365)
79(0.263)
108(0.540)
210(0.700)
0.30
1.898 (1.397, 2.577)
Jonsson
Norway
117/177
10(0.085)
22(0.124)
49(0.419)
75(0.424)
58(0.496)
80(0.452)
0.29
0.826 (0.578, 1.180)
Chena
China
501/461
92(0.184)
73(0.158)
231(0.461)
235(0.510)
178(0.355)
153(0.332)
0.27
1.004 (0.837, 1.204)
Asian
851/1258
133(0.156)
165(0.131)
385(0.452)
611(0.486)
333(0.391)
482(0.383)
0.19
1.094 (0.953, 1.256)b
1.101 (0.949, 1.277)c
Caucasian
409/653
39(0.095)
54(0.083)
156(0.381)
234(0.358)
214(0.523)
365(0.559)
0.06
1.080 (0.596, 1.954)d
Overall
1260/1911
172(0.137)
219(0.115)
541(0.429)
845(0.442)
547(0.434)
847(0.443)
0.71
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
(MDR) [15].
Furthermore, bipolar disorder is a complex disease resulting
frombothgeneticandenvironmentfactors.Epigeneticmechanisms
such as DNA methylation also play a role in bipolar disorders [2,30]
and the MTHFR C677T polymorphism has been found to affect DNA
methylation[12,28].However,associationstudyandmeta-analysis
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-
derlischaracterizedbyrecurrentepisodesofdepressionandmania
whereas bipolar disorder ll disorder is characterized by recurrent
depression and hypomania, a milder form of mania [4]. 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.
Acknowledgements
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
disorderpatients.ThisworkwassupportedbytheKnowledgeInno-
vation Program of the Chinese Academy of Sciences, Grant No.
KSCX2-YW-R-01.
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