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Dopamine beta-hydroxylase gene polymorphisms and psychotic symptoms in schizophrenia.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:944 –945 (2007)
Letter to the Editor
Dopamine Beta-Hydroxylase Gene Polymorphisms and
Psychotic Symptoms in Schizophrenia
J.K. Park,1 J.W. Kim,2 H.J. Lee,3 J.H. Chung,4 E.Y. Ha,5 D.J. Oh,6 J.Y. Song2*
1
Department of Psychiatry, Kyung Hee University East-West Neo Medical Center, Seoul, Korea
Department of Neuropsychiatry, Kyung Hee University Hospital, Seoul, Korea
3
Department of Pharmacology, College of Medicine, Kangwon National University, Chunchon, Korea
4
Kohwang Medical Research Institute, College of Medicine, Kyung Hee University, Seoul, Korea
5
Department of Biochemistry and Molecular Biology, College of Medicine, Kyung Hee University, Seoul, Korea
6
Miso Clinic, Seoul, Korea
2
Please cite this article as follows: Park JK, Kim JW,
Lee HJ, Chung JH, Ha EY, Oh DJ, Song JY. 2007.
Dopamine Beta-Hydroxylase Gene Polymorphisms
and Psychotic Symptoms in Schizophrenia. Am J Med
Genet Part B 144B:944–945.
To the Editor:
Dear Sir,
Dopamine beta-hydroxylase (DBH) is a key enzyme in the
conversion of dopamine to norepinephrine. Low DBH activity is closely related to vulnerability to positive psychotic
symptoms in several psychiatric disorders [Meltzer et al.,
1976] and to clinically important characteristics of schizophrenia, including the prognosis and treatment response [Van
Kammen et al., 1982]. It has been suggested that genetic
variants associated with low plasma DBH levels are also
associated with differences in the vulnerability to psychotic
symptoms and with phenotypic variability in schizophrenia
and other psychiatric disorders [Williams et al., 1999]. To
assess the role of the DBH gene in modifying the vulnerability
to psychotic symptoms, we investigated three polymorphisms
of the DBH gene known to be associated with plasma DBH
levels in Korean schizophrenic patients and healthy controls:
DBH50 -ins/del, DBH-1021C/T (rs 1611115), and DBH444G/A
(rs 1108580).
The subject group consisted of 140 Korean patients with
schizophrenia and the control group comprised 161 healthy
Koreans. All patients in the subject group were diagnosed with
schizophrenia according to the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV). The diagnosis was
based on all of the clinical information and the OPCRIT system.
This study received approval from the local ethics committee,
and written informed consent was obtained from all subjects.
The patient group was subdivided according to psychotic
symptoms: hallucinations, delusions, and auditory hallucinations and persecutory delusions. The genotype and allele
frequencies of the control and patient groups were analyzed by
the chi-square test and Fisher’s exact test using the Statistical
Analysis System program (version 8.0; SAS Institute, Cary,
Grant sponsor: Kyung Hee University Research Fund; Grant
number: KHU-20031111.
*Correspondence to: J.Y. Song, Department of Neuropsychiatry, Kyung Hee University Hospital, 1 Hoegi-dong, Dongdaemoon-gu, Seoul 130-702, Korea. E-mail: parkdawit@naver.com
Received 21 August 2006; Accepted 23 January 2007
DOI 10.1002/ajmg.b.30516
ß 2007 Wiley-Liss, Inc.
NC); haplotype frequencies between the polymorphisms were
estimated using the Estimated Haplotype frequencies (EH)
program (version 1.14).
The genotype distributions and allele frequencies of the
three polymorphisms did not differ significantly between
the schizophrenic patients and healthy controls (Table I). In
the haplotype analysis, no significant difference between each
subgroup of schizophrenic patients and the controls was
observed. The results imply that the DBH gene does not play
a causative role in schizophrenia, and are consistent with a
previous DBH study [Jönsson et al., 2003] that suggested no
major involvement of the DBH gene in schizophrenia.
In contrast, Sternberg et al. [1983] found that low DBH
activity was significantly related to psychotic symptoms, such
as hallucinations and delusions. Since DBH50 -ins/del, DBH1021C/T, and DBH444G/A are known to be associated with low
plasma DBH activity, and DBH50 -ins/del and DBH444G/A are
both in strong linkage disequilibrium with DBH-1021C/T
[Williams et al., 1999], we examined the association of these
three polymorphisms with the vulnerability to psychotic
symptoms: hallucinations, delusions, and auditory hallucinations and persecutory delusions (the most common hallucinations and delusions in schizophrenia). No difference in the
genotype distributions and allele frequencies of the three
polymorphisms was observed between patients with hallucinations and the controls or between patients with delusions
and the controls.
However, we found a significant difference in the genotype distribution of the DBH444G/A polymorphism between
schizophrenic patients with both auditory hallucinations and
persecutory delusions and the controls (P ¼ 0.037). In addition,
the GG genotype was significantly more frequent (P ¼ 0.02)
in the schizophrenic patients with auditory hallucinations
and persecutory delusions (6.7%) compared to the controls
(0.6%).
Sapru et al. [1989] reported a significant decrease in the
serum DBH activity in patients with psychotic major depressive disorder compared to controls. Cubells et al. [2000]
suggested that a specific haplotype associated with low plasma
DBH activity was associated with greater vulnerability to
cocaine-induced paranoia. Yamamoto et al. [2003] suggested
that the DBH gene modulates the psychotic symptoms of
schizophrenia. Based on these premises, low DBH activity and
the associated genetic variants of the DBH gene may be
associated with the psychotic symptoms of some psychiatric
disorders. Evidence suggests that low DBH activity leads to
less efficient conversion of dopamine to norepinephrine, and
may elevate the dopamine/norepinephrine ratio in the brain,
contributing to the emergence of psychotic symptoms [Cubells
and Zabetian, 2004].
Wood et al. [2002] suggested that the GG genotype protects
against the development of psychosis in the presence of a major
DBH Gene and Phenotypic Variation in Schizophrenia
945
0
TABLE I. Genotype Distributions and Allele Frequencies of 5 -ins/del, 1021C/T, and 444G/A Polymorphisms of DBH Gene in
Schizophrenic Patients and Controls*
Schizophrenic patients
Psychotic symptoms
Controls
Total
Hal.(þ)
Hal.()
Del.(þ)
Del.()
A.H.&P.D.a
n¼161
n¼140
n¼80
n¼60
n¼115
n¼25
n¼60
46 (32.9)
64 (45.7)
30 (21.4)
24 (30.0)
36 (45.0)
20 (25.0)
22 (36.7)
28 (46.6)
10 (16.7)
37 (32.2)
53 (46.1)
25 (21.7)
9 (36.0)
11 (44.0)
5 (20.0)
20 (33.3)
23 (38.3)
17 (28.4)
0.56
0.44
0.53
0.47
0.6
0.4
0.55
0.45
0.58
0.42
0.53
0.47
6 (4.3)
43 (30.7)
91 (65.0)
4 (5.0)
26 (32.5)
50 (62.5)
2 (3.4)
17 (28.3)
41 (68.3)
5 (4.4)
35 (30.4)
75 (65.2)
1 (4.0)
8 (32.0)
16 (64.0)
2 (3.4)
20 (33.3)
38 (63.3)
0.2
0.8
0.21
0.79
0.18
0.82
0.2
0.8
0.2
0.8
0.2
0.8
104 (74.3)
32 (22.8)
4 (2.9)
57 (71.2)
19 (23.8)
4 (5.0)
47 (78.3)
13 (21.3)
0 (0.0)
84 (73.0)
27 (23.5)
4 (3.5)
20 (80.0)
5 (20.0)
0 (0.0)
42 (70.0)
14 (23.3)
4 (6.7)
0.86
0.14
0.83
0.17
0.89
0.11
0.85
0.15
0.9
0.1
0.82
0.18
DBH50 -ins/del
Genotype
ins/ins
39 (24.2)
ins/del
85 (52.8)
del/del
37 (23.0)
Allele frequency
ins
0.51
del
0.49
DBH-1021C/T
Genotype
T/T
3 (1.8)
T/C
60 (37.3)
C/C
98 (60.9)
Allele frequency
T
0.21
C
0.79
DBH444G/A
Genotype
A/A
114 (70.8)
A/G
46 (28.6)
G/G
1 (0.6)
Allele frequency
A
0.85
G
0.15
*Hal., hallucinations; Del., delusions; A.H., auditory hallucinations; P.D., persecutory delusions. Values are n (%).
a
Genotype distributions of DBH444G/A polymorphism in schizophrenic patients who presented both auditory hallucinations and persecutory delusions
(boxed square) versus controls, w2 ¼ 7.507, df ¼ 2, P ¼ 0.037.
depressive episode, which is in contrast to our results. The
reason why the GG genotype seems to play such contradictory
roles—a protective factor in Wood et al. (2002) and a risk factor
in our study—is not clear; however, we postulate that the
lower GG genotype frequency in Asians (2.6%) compared to
Europeans (35.2%) (http://www.ncbi.nlm.nih.gov/SNP/), the
presence of other psychiatric disorders, and differences in the
type of psychotic symptoms are responsible. Although the role
of the DBH444GG genotype remains to be elucidated, this
result supports the previous hypothesis that genetic variants
of the DBH gene are a risk factor for the development of
psychotic symptoms.
In conclusion, with the provision that our results must be
interpreted with the usual caution for association studies, our
study provides evidence that the DBH gene plays a role in
increasing the vulnerability to psychotic symptoms.
with low plasma dopamine b-hydroxylase activity, also associates with
cocaine-induced paranoia. Mol Psychiatry 5:56–63.
Jönsson EG, Jamra RA, Schumacher J, Flyckt L, Edman G, Forslund K,
Mattila-Evenden M, Rylander G, Åsberg M, Bjerkenstedt L, Wiesel F,
Propping P, Cichon S, Nöthen MM, Sedvall GC. 2003. No association
between a putative functional promoter variant in the dopamine
b-hydroxylase gene and schizophrenia. Psychiatr Genet 13:175–178.
Meltzer HY, Hyong HW, Carroll BJ, Rosso P. 1976. Serum dopamine-bhydroxylase in the affective psychoses and schizophrenia: Decreased
activity in unipolar psychotically depressed patients. Arch Gen
Psychiatry 33:585–591.
Sapru MK, Rao BS, Channabasavanna SM. 1989. Serum dopamine-betahydroxylase activity in clinical subtypes of depression. Acta Psychiatr
Scand 80:474–478.
Sternberg DE, van Kammen DP, Lerner P, Ballenger JC, Marder SR, Post
RM, Bunney WE. 1983. CSF dopamine-b-hydroxylase in schizophrenia:
Low activity associated with good prognosis and good response to
neuroleptic treatment. Arch Gen Psychiatry 40:743–747.
Van Kammen DP, Lerner P, Bunney WE. 1982. Schizophrenia: Dopamine bhydroxylase activity and treatment response. Science 216:1423–1425.
ACKNOWLEDGMENTS
This research was supported by the Kyung Hee University
Research Fund in 2003 (KHU-20031111).
REFERENCES
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beta, polymorphism, dopamine, hydroxylase, psychotic, genes, symptom, schizophrenia
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