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Analysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Analysis of Genetic Variations in the RGS9 Gene
and Antipsychotic-Induced Tardive Dyskinesia
in Schizophrenia
Ying-Jay Liou,1,2 Mao-Liang Chen,3 Ying-Chieh Wang,3,4 Jen-Yeu Chen,3 Ding-Lieh Liao,5 Ya-Mei Bai,1
Chao-Cheng Lin,6 Tzu-Ting Chen,3 Geng-Han Mo,3 and I-Ching Lai3,4*
1
Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
2
3
Department of Psychiatry, Yuli Mental Health Research Center, Yuli Veterans Hospital, Yuli, Hualien, Taiwan
4
Institute of Medical Science, Tzu Chi University, Hualien, Taiwan
Department of Psychiatry, Pali-Psychiatric Hospital, Taipei, Taiwan
5
6
Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
Received 4 March 2008; Accepted 29 April 2008
Some patients treated chronically with antipsychotics develop
tardive dyskinesia (TD), an abnormal involuntary movement
disorder. Typical antipsychotics block D2 dopamine receptors
(D2DR) and produce D2DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal
termination of G-protein-coupled D2DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic
agonists induced severe dyskinesia only in RGS9 knock-out mice
but not in normal mice. Therefore, variety in the human RGS9
gene may be related to susceptibility to TD. In this study,
schizophrenic inpatients receiving long-term antipsychotic
treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom
abnormal involuntary movements were absent (non-TD group)
and those who showed persistent TD (TD group) were enrolled.
There were 407 patients in the study sample (TD ¼ 252; nonTD ¼ 155) and seven single nucleus polymorphisms (SNPs) in
the RGS9 gene were genotyped for each subject. Genotype and
allelic distributions of SNPs did not differ between the TD and
non-TD groups in this study, with the exception that a weak
trend of allelic association was seen with rs4790953 (P ¼ 0.0399).
In the haplotype analysis, a significant association of the AGG
haplotype (rs8077696–rs8070231–rs2292593) of the RGS9 gene
was found (permutation P ¼ 0.007), and this is worthy of replication and further study. Ó 2008 Wiley-Liss, Inc.
Key words: RGS; tardive dyskinesia; schizophrenia; antipsychotic; haplotype
INTRODUCTION
Tardive dyskinesia (TD) is an abnormal involuntary movement
disorder characterized by a variable combination of the following:
persistent orofacial and lingual dyskinesia, tics, grimacing, truncal
Ó 2008 Wiley-Liss, Inc.
How to Cite this Article:
Liou Y-J, Chen M-L, Wang Y-C, Chen J-Y,
Liao D-L, Bai Y-M, Lin C-C, Chen T-T, Mo
G-H, Lai I-C. 2009. Analysis of Genetic
Variations in the RGS9 Gene and
Antipsychotic-Induced Tardive Dyskinesia in
Schizophrenia.
Am J Med Genet Part B 150B:239–242.
or axial muscle involvement, chorea and athetosis. Approximately
13–36% of patients treated chronically with antipsychotics, but less
than 2% of psychiatric patients who have never been exposed to
antipsychotics, develop TD [Woerner et al., 1991]. Typical antipsychotics act by blocking D2 dopamine receptors (D2DR); therefore, the pathophysiology of TD may be hidden in the signal
pathway of dopamine transmission in the brain. Chronic inhibition
of dopamine signaling along the nigrostriatal dopamine pathway
can increase the proportion of high-affinity D2DR and produce
D2DR supersensitivity [Rubinstein et al., 1990], leading to abnormal signaling and abnormal involuntary movements.
Grant sponsor: National Science Council, Taiwan; Grant numbers: NSC952314-B480-002-MY3, NSC96-2314-B-480-002; Grant sponsor: Yu-Li
Veterans Hospital, Hualien, Taiwan; Grant numbers: VHYL-97-02,
VHYL-97-03.
*Correspondence to:
Dr. I-Ching Lai, Department of Psychiatry, Yuli Veterans Hospital, No. 91,
Shin-Shin St., Yuli, Hualien 981, Taiwan. E-mail: lai_0228@yahoo.com.tw
Published online 11 June 2008 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.b.30796
239
240
The receptors for dopamine are members of the G-proteincoupled receptor (GPCR) superfamily [Missale et al., 1998], and
GPCR signal termination can be enhanced by members of a family
of proteins called regulators of G-protein signaling (RGSs)
[Berman and Gilman, 1998]. Mice with a null mutation in the
RGS9 gene showed augmented locomotor responses to psychostimulants, but viral-mediated overexpression of RGS9-2, the RGS9
splice variant, specifically reduced locomotor response to D2DR
agonists [Rahman et al., 2003]. The expression of RGS9-2 is
selectively confined to the striatum [Thomas et al., 1998; Rahman
et al., 1999], the region involved in antipsychotic-induced TD.
Furthermore, the DEP (Disheveled, EGL-10, Pleckstrin homology)
domain of RGS9-2 mediates subcellular colocolization with D2DR,
and such localization may imply a role of RGS9-2 in the suppression
of antipsychotic-induced extrapyramidal symptoms [Kovoor et al.,
2005].
In RGS9 knock-out mice, direct treatment with dopaminergic
agonists only produces minor increases in locomotion; however,
after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induce severe dyskinesia exclusively in RGS9 knockout mice but not in normal mice [Kovoor et al., 2005]. Similarly,
only a few drug-naive schizophrenic patients develop dyskinesia,
but after prolonged antipsychotic treatment, a large proportion of
schizophrenic patients develop TD. Hence, RGS9-2 is very likely to
play an important role in the susceptibility of patients to
antipsychotic-induced TD.
It is impossible to knock out the RGS9 gene in humans to prove
the evidence found in animal models. The percentage of schizophrenics with antipsychotic-induced TD is 13–36%, which is
unlikely resulted from the whole gene deletion of RGS9 in humans.
Besides, the severity of antipsychotic-induced TD varies between
affected individuals; therefore, susceptibility to antipsychoticinduced TD is highly suspected as being associated with genetic
variances in RGS9. To the best of our knowledge, there are no
previous studies of this gene epidemiology, and so we performed
the present study to explore the relationship between the RSG9 gene
and antipsychotic-induced TD in Chinese schizophrenic patients.
MATERIALS AND METHODS
Clinical Assessment
Two senior board-certificated psychiatrists verified the diagnosis of
each inpatient according the criteria of DSM-IV before he/she
entered the study, based on interview, an oral report from family
and/or caregivers, clinical observation and chart records. Demographic and clinical variables were also measured, including gender,
age, cumulative duration of antipsychotic exposure, and daily
dosage of antipsychotics (converted to chlorpromazine (CPZ)
equivalents). The inclusion criteria were: a diagnosis of schizophrenia, persistent treatment with typical antipsychotics over the past
2 years, maintenance on a stable dosage of antipsychotics for at least
6 months. The exclusion criteria were: aged over 65 or under 18
years old; combination with an organic mental disorder, mood
disorder, neurological illness or diabetes mellitus; a history of
substance use (alcohol, amphetamines, or opiates); and previous
exposure to atypical or second-generation antipsychotic treatment.
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
Yuli Veterans Hospital Institutional Review Board had approved
this study in advance, and all patients were fully informed about the
study before giving informed consent.
The senior psychiatrists (Dr. Lai IC, Dr. Bai YM, Dr. Lin CC, Dr.
Liao DL, and Dr. Chen JY) involved in the study were experienced in
using the Abnormal Involuntary Movement Scale (AIMS). TD was
defined as of a mild degree of involuntary movement in two or
more body regions or of a moderate to severe degree in one or more
areas of the body. For confirmation of the diagnosis of TD, all
patients were rated twice over a 3-month interval based on the
Research and Diagnostic Criteria for persistent TD [Schooler and
Kane, 1982]. Non-TD was defined as the absence of any abnormal
involuntary movements as assessed in two successive interviews.
In order to maintain assessment consistency, each patient was
evaluated by the same rater. All raters completed their assessments
before DNA genotyping and were therefore blind to the genotypes
of patients.
Marker Selection and Genotyping
We selected genotyped genetic markers in the combined HCB
population from the International HapMap Project (http://
www.hapmap.org/). Seven single nucleotide polymorphisms
(SNPs) have minor allele frequencies of greater than 10% (listed
in Table I), including rs8077696, rs8070231, rs2292593, rs2292592,
rs9916525, rs1122079, and rs4790953.
Genomic DNA was extracted from the white blood cells of
peripheral venous blood, and the genotype of each SNP was
determined by TaqManÒ assay. TaqManÒ probes and Universal
PCR Master Mix were obtained from Applied Biosystems (http://
www.appliedbiosystems.com). After amplification, the allelic specific fluorescence was measured using ABI PRISMÒ 7500 Sequence
Detector Systems.
Statistical, Single Marker, and Haplotype Analysis
We used an independent t-test to evaluate the differences in the
means of the continuous variables between groups, and the chisquare test to evaluate the independence between categorical
variables. Deviation from Hardy–Weinberg Equilibrium for each
SNP was checked by a chi-square goodness of fit test with the degree
of freedom of 1. The threshold of significance was set as P < 0.05. All
analyses were performed using SPSS 10.0 for Microsoft Windows.
Information for pairwise linkage disequilibrium (LD) was evaluated using the SNP AlyzeÒ V3.2 program (Dynacom Co., Ltd.,
Kanagawa, Japan). We also used this program to infer the haplotype
frequency and to examine the difference in haplotype frequencies
between the TD and non-TD groups. The significance level of the
analyses obtained from SNP AlyzeÒ V3.2 was set as P < 0.05 after
100,000 permutation tests.
RESULTS
After the 3-month interval evaluations, 407 patients with schizophrenia (252 with persistent TD and 155 without TD) were
recruited to the study. There was no significant difference
between the groups in the distribution of gender (male/female,
LIOU ET AL.
241
TABLE I. Distribution of the RGS9 Genotypes and Alleles in the TD and Non-TD Groups
Genotype
SNP ID
rs8077696
Allele
1/2
C/A
Position
Intron 3
rs8070231
A/G
Intron 4
rs2292593
A/G
Intron 4
rs2292592
C/T
Intron 7
rs9916525
C/T
Intron 8
rs1122079
T/A
Intron 8
rs4790953
A/C
30 -flanking
region
Group
TD (%)
Non-TD (%)
TD (%)
Non-TD (%)
TD (%)
Non-TD (%)
TD (%)
Non-TD (%)
TD (%)
Non-TD (%)
TD (%)
Non-TD (%)
TD (%)
Non-TD (%)
1/1
107 (43.7)
62 (40.5)
98 (40.0)
54 (34.8)
107 (43.3)
53 (34.6)
119 (47.8)
68 (44.2)
109 (45.0)
61 (39.6)
120 (48.2)
67 (43.5)
130 (53.1)
66 (43.1)
Allele
1/2
111 (45.3)
72 (47.1)
110 (44.9)
67 (43.2)
104 (42.1)
76 (49.7)
109 (43.8)
68 (44.2)
113 (46.7)
73 (47.4)
112 (45.0)
70 (45.5)
100 (40.8)
72 (47.1)
TD ¼ 97/58, non-TD ¼ 153/99, P ¼ 0.753), age (years [mean SD], TD ¼ 47.9 9.2, non-TD ¼ 47.2 9.2, P ¼ 0.464), cumulative length of antipsychotic exposure (years [mean SD], TD ¼
21.0 8.3, non-TD ¼ 20.2 7.9, P ¼ 0.325) or current daily antipsychotic dosage (mg/day [mean SD], TD ¼ 699.1 477.1, nonTD ¼ 778.1 456.3, P ¼ 0.128). The distributions of the RGS9
genotypes in the TD and non-TD groups were all in Hardy–
Weinberg equilibrium. Genotype and allelic distributions of SNPs
in the study did not differ between the TD and non-TD groups, with
the exception of a weak trend of allelic association seen with
rs4790953 (P ¼ 0.0399) (Table I).
Pairwise LD analysis and haplotype block determination revealed that there were two blocks across the studied genomic region
in which the RGS9 gene is located (Fig. 1). Measurement of pairwise
LD showed that the first 3 SNPs were in strong LD with each other
and were located in the sample block (haplotype block 1). Another
block (haplotype block 2) was constructed by rs2292592,
rs9916525, and rs1122079. In the haplotype-based analyses, the
haplotypes in the two blocks were analyzed separately according to
their locations in the specific block. The results of the comparisons
of haplotype distribution in haplotype block 1 between TD and
non-TD groups are listed in Table IIa. Individual haplotype
analysis showed that the haplotype AGG was associated with
non-TD (permutation P-value ¼ 0.007). For the genetic variation
in block 2, no significant difference in haplotype distribution was
found between the groups in global analysis (permutation
P ¼ 0.162).
2/2
27 (11.0)
19 (12.4)
37 (15.1)
34 (21.9)
36 (14.6)
24 (15.7)
21 (8.4)
18 (11.7)
20 (8.3)
20 (13.0)
17 (6.8)
17 (11.0)
15 (6.1)
15 (9.8)
P-value
0.802
0.200
0.217
0.518
0.255
0.239
0.109
1
325 (66.3)
196 (64.0)
306 (62.4)
175 (56.5)
318 (64.3)
182 (59.5)
347 (69.7)
204 (66.2)
331 (68.4)
195 (63.3)
352 (70.7)
204 (66.2)
360 (73.5)
204 (66.7)
2
165 (33.4)
110 (36.0)
184 (37.6)
135 (43.5)
176 (35.7)
124 (49.5)
151 (30.3)
104 (33.8)
153 (31.6)
113 (36.7)
146 (29.3)
104 (33.8)
130 (26.5)
102 (33.3)
P-value
0.5116
0.0915
0.1645
0.3068
0.1403
0.1846
0.0399
striatum [Rahman et al., 2003; Kovoor et al., 2005]. RGS9 knockout mice show dyskinesia after antipsychotic treatment but seem to
be normal while they are drug-nai?ve; therefore, RGS9 may be a
modulator of the dopamine pathway. The reason why some patients develop TD after antipsychotic treatment and others do not is
very likely due to genetic differences in RGS9.
Our results showed that one SNP, rs4790953, was found to have
a weak trend of allelic association with TD, but this was insigni-
DISCUSSION
Although the cause of TD remains obscure, the brain-specific
protein, RGS9-2, is a good candidate for the pathogenesis of TD.
Chronic administration of antipsychotics results in increased D2DR
and dopamine sensitivity [Samaha et al., 2007] and increases the
possibility of developing TD [Woerner et al., 1991]. RGS9-2 has
been suggested as colocalizing with D2DR and terminating the
signal transduction of G-protein in the dopamine pathway in the
FIG. 1. Illustration of the organization of the haplotype blocks
constructed by the seven studied single nucleotide
polymorphisms (SNPs) in the RSG9 gene.
242
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE II. Haplotype Analysis of (a) Block 1
(rs8077696–rs8070231–rs2292593) and (b) Block 2
(rs2292592–rs9916525–rs1122079) of the RGS9
Gene of the TD and Non-TD Groups
Haplotype
Block 1
CAA
AGA
CAG
CGG
AGG
Global
Block 2
CCT
TTA
Global
TD (%)
Non-TD (%)
Permutation P-value
54.4
9.0
7.5
7.0
22.1
62.9
0.0
0.0
0.0
37.1
0.276
0.124
0.243
0.403
0.007*
0.079
70.0
30.0
64.9
35.1
0.160
0.160
0.162
*P < 0.05.
ficant after Bonferroni correction. In the haplotype analysis, a
significant association of the AGG haplotype (rs8077696–
rs8070231–rs2292593) of the RGS9 gene was found
(permutation P ¼ 0.007), and this is worthy of replication and
further study. The function of the AGG haplotype
(rs8077696–rs8070231–rs2292593) of the RGS9 gene is unknown;
it may alter the binding efficiency of RGS9-2 to DRD2 or other
genetic variations near any one of these SNPs (rs8077696,
rs8070231, and rs2292593), and may play an important role in the
development of TD.
However, it is difficult to replicate the present study in Taiwan.
First, the non-TD control group patients must take typical antipsychotics chronically but have no symptoms of TD development;
however, more and more schizophrenic patients take atypical
antipsychotics as a first-line treatment, due to their condition being
unmanageable with typical antipsychotics, or to the extrapyramidal
symptoms caused by typical antipsychotics. Therefore, it is becoming increasingly difficult to recruit non-TD controls. Second,
although persistent TD is not rare, it is not frequently seen. Finally,
we have to recruit our samples from three large psychiatric institutes in order to obtain enough subjects for meaningful study.
Because the risk of false positive is high in this kind of study design;
therefore, we hope that our results study can be replicated in other
countries or other populations.
In conclusion, our findings support the involvement of genetic
variations of the RGS9 gene in the susceptibility to antipsychoticinduced TD.
ACKNOWLEDGMENTS
This work was supported by grants NSC95-2314-B480-002-MY3
and NSC96-2314-B-480-002 from the National Science Council,
Taiwan, and grants VHYL-97-02 and VHYL-97-03 from Yu-Li
Veterans Hospital, Hualien, Taiwan.
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