No evidence of association between a functional polymorphism in the MTHFR gene and childhood-onset mood disorders

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0.07 in our Hispanic-Caucasian sample and in Wong
et al. In the HapMap Caucasian sample, this marker
had a minor allele frequency of 0.1. For rs1880916,
Wong et al. found a minor allele frequency of 0.12,
compared to 0.17 in our sample, whereas the minor
allele frequency was 0.2 in the HapMap Caucasian
sample. These data suggest that the samples in both
studies are similar.
Acknowledgments
This work was supported by the National Institute of
Mental Health to SPH (MH072802), the State of New
York (PJM) and Grant CA 94919 (SLS) from the
National Cancer Institute. STAR*D was funded by
NIMH via contract (N01MH90003) to the University
of Texas Southwestern Medical Center at Dallas
(A John Rush, PI).
KS Teranishi
1
, SL Slager
2
, H Garriock
1
, JB Kraft
1
,
EJ Peters
1
, MS Reinalda
2
, GD Jenkins
2
,
PJ McGrath
3
and SP Hamilton
1
1
Department of Psychiatry and Institute for Human
Genetics, University of California, San Francisco, CA,
USA;
2
Department of Health Sciences Research, Mayo
Clinic, Rochester, MN, USA and
3
Department of
Psychiatry, New York State Psychiatric Institute,
Columbia University College of Physicians and
Surgeons, New York, NY, USA
E-mail: SteveH@lppi.ucsf.edu
References
1 Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Cantor
RM et al. Proc Natl Acad Sci USA 2006; 103: 15124–15129.
2 Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim
HA et al. Controlled Clin Trials 2004; 25: 119–142.
3 Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D,
Ritz L et al. Am J Psychiatry 2006; 163: 28–40.
4 Kraft JB, Peters EJ, Slager SL, Jenkins GD, Reinalda MS, McGrath PJ
et al. Biol Psychiatry 2007; 61: 734–742.
No evidence of association
between a functional
polymorphism in the
MTHFR gene and
childhood-onset mood
disorders
Molecular Psychiatry (2007) 12, 1063–1064;
doi:10.1038/sj.mp.4002071
Several lines of evidence implicate the role of folate
pathway in the aetiology of depression. These include
evidence that folic acid has shown promise as an
adjuvant in complimenting antidepressant treatment,
and the 5,10-methylenetetrahydrofolate reductase
(MTHFR) gene has been associated with depression.
1
Further, genome scans for depression, including
early-onset depression, indicate linkage to 1p36.2,
2,3
the location of the MTHFR gene. To investigate the
role of the MTHFR gene in early-onset depression, we
tested a functional polymorphism, C677T, as a risk
factor in a large Hungarian sample of 583 families
with children diagnosed with a mood disorder before
the age of 15.
MTHFR is an enzyme involved in the metabolism
of folic acid, by catalysing the reduction of 5,10-
methylenetetrahydrofolate to 5-methyl tetrahydrofo-
late. This reaction acts as a methyl donor in the
conversion of homocysteine, a product formed during
methylation reactions, to methionine. Methionine is a
precursor for S-adenosyl methionine, an important
enzyme in the catabolism of methylation reactions in
the central nervous system. Impairment in the
conversion of homocysteine into methionine results
in an increase in homocysteine levels, which can be
deleterious through the inhibition of methylation
reactions if left to accumulate.
1
There is a common C677T functional variant in the
MTHFR gene resulting in an amino-acid transition
from alanine to valine. This change leads to a
thermolabile version of MTHFR with reduced enzy-
matic activity.
4
There are a number of studies that
suggest an association between the low-activity allele
(677T) and major depression, however there are also a
number of negative reports.
1
Recently, Lewis et al.
5
performed an association in a large female population
sample and found an association between the MTHFR
677T allele and an increase in self-reported depres-
sion symptoms. To complement their analysis, they
performed a meta-analysis on all previous reports,
finding a combined odds ratio of 1.36 for the 677T
allele in depression, thus indicating that this genetic
variant is a small but significant risk factor for
depression.
For this study, C677T (rs1801133) was genotyped in
583 nuclear families ascertained through a child or
adolescent with a diagnostic and statistical manual of
mental disorders IV diagnosis of a mood disorder
(unipolar or bipolar) before 15 years of age (child-
hood-onset mood disorder). Families consisted of 717
affected children (583 probands and 134 affected
siblings). The recruitment and assessment of this
sample has been described previously.
6
Genotyping
was performed using the TaqMan 5
0
nuclease assay
(Applied Biosystems, Foster City, CA, USA) (ABI
probe ID, C_1202883_20). Transmission disequili-
brium test analysis was performed using TDT phase.
7
Power calculations were permutated by the Quanto
program (http://hydra.usc.edu/gxe). The minor allele
frequency for this marker was 0.35 in this sample,
which is consistent with previous studies and no
deviation from the Hardy–Weinberg equilibrium was
observed.
Letters to the Editor
1063
Molecular Psychiatry

No significant association was observed between
childhood-onset mood disorder and the 677T allele
(T 224: NT 246: w
2
= 1.03 P = 0.31) despite this sample
having 85% power to detect the odds ratio of 1.36
obtained from the recent meta-analysis.
5
Thus, the
results of this study fail to support the conclusion of
the recent meta-analysis.
Inconsistencies in the outcome of investigations
into the association between the 677T allele and
depression could be attributed to the indirect nature
of the pathological mechanism of this polymorphism.
The 677T allele has been found to be associated with
an increase in homocysteine and a decrease in folate,
but both within the normal range. However, under
sub-optimum folate status, the 677T allele is asso-
ciated with increased plasma homocysteine
8
and
global hypomethylation,
9
suggesting the existence of
a gene  nutrient interaction.
Elevated homocysteine levels have been associated
with a wide range of phenotypes including dementia,
arteriosclerosis, cardiovasculature disease, cognitive
impairment, as well as depression. Interestingly,
many of these phenotypes are also associated with
the 677T allele.
10
Furthermore, extensive hypomethy-
lation, which is probably a consequence of elevated
homocysteine levels, could have diverse implications
through the random expression of previously quies-
cent genes, and whether or not a change in methyla-
tion status contributes to psychopathology may
depend on individual genetic architecture.
Elevated maternal levels of homocysteine during
pregnancy are associated with premature delivery,
pre-eclampsia and placental damage that may influ-
ence oxygen delivery to the fetus, risk factors
indicated in a number of neuropsychiatric disorders.
Further, a recent report suggested that maternal
homozygosity of the T allele may be associated with
an increase in imprinting defects in their offspring.
11
Thus, we tested for an excess of homozygous 677T
mothers in our sample by comparing the genotype
and allele frequencies of mothers and fathers. We
found no significant difference between these two
groups.
While it is evident that the 677T allele does not
confer risk to the development of childhood-onset
mood disorder in this sample, the presence of an
interaction between folate status and C677T genotype
may explain the previous inconsistent findings in the
literature regarding depression. Consequently, certain
studies may have an enrichment of depressed patients
who are more vulnerable to folate changes, biasing the
association results in specific populations. Another
consideration is the possibility that excess homocys-
teine is contributing to depression related to vascular
dysfunction in older populations.
12
To conclude,
further exploration of this polymorphism and the
interaction with folate status, as well as other
variables, is required in depressed patient popula-
tions. However, the results of this study infer that the
MTHFR genotype is unlikely to be a considerable risk
factor for the development of childhood-onset mood
disorder.
EL Dempster
1
, E Kiss
2
, K Kapornai
2
, G Daro
´
czy
2
,
L Mayer
2
, I Baji
3
, Z Tamas
3
, J Gadoros
3
, JL Kennedy
4
,
A Vetro
´
2
, M Kovacs
5
and CL Barr
1,6
, The International
Consortium for Childhood-Onset Mood Disorders
1
Toronto Western Research Institute, Toronto, ON,
Canada;
2
University of Szeged, Szeged, Hungary;
3
Vadaskert Hospital, Budapest, Hungary;
4
Centre for
Addiction and Mental Health, Toronto, ON, Canada;
5
School of Medicine, University of Pittsburgh,
Pittsburgh, PA, USA and
6
The Hospital for Sick
Children, Toronto, ON, Canada
E-mail: cbarr@uhnres.utoronto.ca
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Eur J Hum Genet 2006; 14: 752–758.
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Psychol Med 2001; 31: 1403–1412.
Letters to the Editor
1064
Molecular Psychiatry