Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia

Psychiatry Research 127 (2004) 1–7

Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia Chima Matsumotoa,*, Takahiro Shinkaia, Hiroko Horia, Osamu Ohmoria,b, Jun Nakamuraa a

Department of Psychiatry, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, 807-8555, Japan b Wakato Hospital, Wakamatsu-ku, Kitakyushu, 808-0132, Japan Received 12 February 2003; received in revised form 5 January 2004; accepted 24 March 2004

Abstract Several lines of evidence suggest that tardive dyskinesia (TD) may be associated with altered dopaminergic neurotransmission. We hypothesized that deranged dopamine degradation enzyme activities might be related to the susceptibility to TD through altered dopaminergic neurotransmission in the central nervous system. In the present study, we investigated the relationship between the gene polymorphisms of three dopamine degradation enzymes and TD. We genotyped the valineymethionine polymorphism of codon 108y158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the AyG polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia. No significant difference was found in total scores on the Abnormal Involuntary Movement Scale (AIMS) among the subject groups, sorted according to the COMT, MAOA and MAOB genotypes. Moreover, no significant difference was found in allele frequencies between patients with TD and patients without TD for any of the polymorphisms. As both COMT and MAO genes are involved in degrading catecholamines, we also sought evidence for additive and epistatic effects, but none was observed. Our data, therefore, do not support the hypothesis that polymorphisms in COMT, MAOA, and MAOB genes are involved individually or in combination in the predisposition to TD. 䊚 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Schizophrenia; Tardive dyskinesia; Genetic association; Polymorphism; Catechol-O-methyltransferase; Monoamine oxidase A; Monoamine oxidase B

1. Introduction Tardive dyskinesia (TD) is an involuntary movement disorder that occurs as a side effect of chronic antipsychotic medication. Although the *Corresponding author. Tel.: q81-93-691-7253; fax: q8193-692-4894. E-mail address: [email protected] (C. Matsumoto).

pathophysiology of TD is not yet understood, a number of hypotheses have been proposed, including altered dopaminergic neurotransmission (Tarsy and Baldessarini, 1977; Klawans et al., 1980; Gerlach and Casey, 1988), GABA insufficiency (Casey, 2000), and structural abnormalities that are associated with antipsychotic treatment, such as change in the volume of the caudate nucleus,

0165-1781/04/$ - see front matter 䊚 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2004.03.011

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which modulates motor function (Chakos et al., 1994; Corson et al., 1999) or free radical-mediated neuronal injury (Andreassen and Jorgensen, 2000). One hypothesis is that there may be functional excess in the activity of dopamine as a synaptic neurotransmitter in the central nervous system (Tarsy and Baldessarini, 1977; Klawans et al., 1980). Moreover, TD has been considered to be related to dopamine receptor site hypersensitivity, which is induced by chronic receptor site blockade by treatment with antipsychotic drugs (Tarsy and Baldessarini, 1977; Klawans et al., 1980). To date, although these hypotheses have limitations (Casey, 2000), the relationship between altered dopaminergic neurotransmission and TD remains a principal focus of research interest. On the basis of the hypothesis of dopamine overactivity, we propose that the altered activities of dopamine-regulating enzymes that are involved in dopamine synthesis and degradation may relate to the pathophysiology of TD. We therefore, analyzed the association between dopamine degradation enzyme gene polymorphisms and TD. We genotyped gene polymorphisms of catecholO-methyltransferase (COMT), monoamine oxidase A (MAOA), and monoamine oxidase B (MAOB), enzymes that play important roles in the degradation of dopamine. Dopamine is catabolized by MAO and COMT, which convert dopamine to 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine, respectively (Norton et al., 2002). The MAOA and MAOB genes are closely linked and located on the X chromosome, Xp11.23-11.4 (Hsu et al., 1989), while the COMT gene has been mapped to chromosome 22q11.2 (Winqvist et al., 1992). In each of these gene sequences, functional significant polymorphisms have been reported. A 30-bp repeat polymorphism in the promoter of MAOA gene has been revealed to be associated with the transcriptional activity of the enzyme in the transfected cells (Sobol et al., 1998; Deckert et al., 1999). With regard to MAOB, significant associations between the AyG polymorphism in intron 13 and levels of MAOB enzyme activity in human platelets (Garpenstrand et al., 2000) and human brain (Balciuniene et al., 2002) have been shown. As for COMT, a valine to methionine substitution, which is caused by a

G to A transition at codon 158 of membranebound COMT (M-COMT) and codon 108 of soluble COMT (S-COMT), has been identified, and it was found that homozygosity for the methionine allele (COMTL allele) leads to a three- to four-fold reduction in enzyme activity compared with homozygosity for the valine allele (COMTH allele). It was also found that heterozygosity shows intermediate activities (Lachman et al., 1996). In the present study, we analyzed the relationship between each of three dopamine degradation enzyme gene polymorphisms and TD in a sample of Japanese patients with schizophrenia. 2. Methods 2.1. Subjects A total of 206 unrelated Japanese patients with schizophrenia (100 women, 106 men, age 54.9"9.4, mean"S.D.) were studied. The diagnosis of schizophrenia using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria was made by consensus of four psychiatrists based on cross-sectional interviews and case records. Informed consent was a requirement for participation, and this study was approved by the Ethics Committee of the University of Occupational and Environmental Health (UOEH). None of the patients had a significant neurological comorbidity, mental retardation, or history of substance abuse. All were inpatients at five local hospitals around the UOEH, and had received antipsychotic treatment for at least 10 years. All of the currently administered antipsychotic doses were calculated into haloperidol equivalents according to the conversions published by Toru (1983) (mean dose, 22.9"23.6 mgyday). Patients treated with atypical antipsychotics were excluded from the present study, as it has been reported that the risk of TD in patients treated with atypical antipsychotics is less than that for those taking typical antipsychotics (Glazer, 2000). 2.2. Assessment of TD TD was evaluated using the Abnormal Involuntary Movement scale (AIMS) (Guy, 1976). The

C. Matsumoto et al. / Psychiatry Research 127 (2004) 1–7

rating was carried out by one of the authors with a cross-sectional evaluation. Subjects with two or more two-point ratings, or one or more three-point ratings, on the first seven items of the AIMS were diagnosed as having probable TD according to the Schooler–Kane criteria (Schooler and Kane, 1982). 2.3. Analysis of the enzyme gene polymorphisms The 30-bp repeat polymorphism in the promoter of the MAOA gene was genotyped using polymerase chain reaction (PCR). The primer sequences were as follows: upstream, 59-CACAAACTGCCTCAGCCTCCTTC-39, and downstream, 59-TGTAGGAGGTGTCGTCCAAGCTG-39. The PCR products of the 176–266 base pair fragments containing the repeat polymorphism were resolved by electrophoresis on 3% agarose gels with ethidium bromide. The AyG polymorphism of MAOB intron 13 was genotyped using PCR followed by restriction fragment length polymorphism (RFLP) analysis. The primer sequences were as follows: upstream, 59-GAGACAGTTACTTAGTCCTTTAGGG-39, and downstream, 59-AGACTCTGGTTCTGACTGCCAGAT-39. The PCR products were digested with MaeIII and resolved by electrophoresis on 3% agarose gels. The polymorphism showed biallele systems as follows: the A allele gave fragments of 98, 41 and 7 base pairs, whereas the G allele gave fragments of 139 and 7 base pairs. The functional COMT gene polymorphism was detected using the method described by Hoda et al. (1996). 2.4. Statistical analysis The fitness of genotype frequency distribution to the Hardy-Weinberg equilibrium was calculated by the x2 goodness-of-fit test. Differences in demographic characteristics, age, duration of illness, current antipsychotic doses, and total AIMS scores were assessed among subjects with three COMT genotypes using the Kruskal–Wallis test. Gender differences were assessed by the x2 test. For the MAOA and MAOB gene polymorphisms, we assessed the differences in these demographic characteristics separately for each gender, because

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males are hemizygous for X chromosome markers. We assessed the differences among female subjects with three MAOA genotypes using the Kruskal– Wallis test. We assessed the differences between male subjects with two MAOA alleles, those between female subjects with two MAOB genotypes, and those between male subjects with two MAOB alleles using the Mann–Whitney U-test. The difference in the allele frequencies for COMT and MAOB gene polymorphisms between subjects with and without TD was analyzed using the x2 test. To evaluate the contingency table with small cell counts, the difference in allele frequency for the MAOA gene polymorphism was analyzed using the Monte Carlo method, and the differences in the allele frequencies for the MAOB gene polymorphism in male and female subjects were analyzed using the Fisher’s exact test. Monte Carlo tests were used to evaluate the contingency table with small cell counts using CLUMP, a computer program (Sham and Curtis, 1995). To study interaction, we restricted the analysis to males and we analyzed the combination of the COMT and MAO gene polymorphisms associated with functional effects. To look for additive effects, we constructed contingency tables of the combinations of COMT and MAOA or MAOB functional genotypes in males and derived x2 statistics for differences in their distributions between patients with TD and without TD (Tables 3 and 4). We also assessed epistasis by testing the functional genotypes at MAOA and MAOB for association with the functional COMT genotype, using the Monte Carlo tests within patients with TD and without TD (Tables 3 and 4). Analysis was restricted to males because it is not possible to construct comparable functional genotypes in females, who have two alleles of MAOA or MAOB. We did not analyze compound genotype data from females separately, as the sample was too small. In addition, one subject with allele 2 of MAOA was excluded from the analysis. 3. Results The overall genotype distribution of the COMT gene polymorphism (Table 1) was within Hardy– Weinberg equilibrium (x2s2.52, d.f.s1, Ps

C. Matsumoto et al. / Psychiatry Research 127 (2004) 1–7

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Table 1 Demographic characteristics of patients according to the three enzyme gene polymorphismsa

COMT HyH HyL LyL P MAOA Femaleb 3y3 3y4 4y4 P Malec 3 4 P MAOB Femaled AyA AyG P Male A G P

N (FyM)

Age (years)

Duration of illness (years)

Current antipsychotic dose (HPD-eq; mgyday)

Total ATMS score

84 (43y41) 103 (48y55) 19 (9y10) 0.82

56.5"8.9 53.8"9.5 54.0"10.7 0.15

29.9"9.1 27.6"9.1 29.9"9.5 0.17

22.9"28.0 22.9"20.0 23.8"20.5 0.57

1.7"2.3 2.1"2.7 2.8"3.6 0.57

37 45 16 –

55.7"11.8 56.9"8.7 55.4"6.6 0.84

27.6"10.3 29.9"8.6 25.7"8.8 0.23

19.8"18.2 26.0"30.9 18.6"14.3 0.90

2.2"2.9 1.6"2.4 2.6"3.1 0.32

63 42 –

53.9"9.7 53.9"8.3 0.89

29.2"9.4 27.8"8.4 0.42

24.5"25.6 20.7"16.0 0.87

2.0"2.2 2.3"3.1 0.69

75 24 –

55.7"10.1 56.7"8.8 0.67

27.9"9.5 29.3"8.9 0.32

25.1"16.8 13.8"11.8 0.06

1.9"2.5 2.0"3.3 0.83

89 17 –

53.9"9.0 53.6"9.3 0.76

29.0"9.3 27.0"7.3 0.26

23.8"23.5 21.6"19.3 0.61

2.1"2.5 2.1"3.1 0.62

a

Abbreviation: HPD-eq, haloperidol equivalents. Two subjects with 2y3 or 4y5 genotypes were excluded. c One subject with allele two was excluded. d One subject with GyG genotype was excluded. b

0.11). Genotype distributions of the MAOA (Table 1: x2s0.18, d.f.s1, Ps0.71) and MAOB gene polymorphism (Table 1: x2s0.37, d.f.s1, Ps 0.54) in female patients were also within Hardy– Weinberg equilibrium. The demographic characteristics of patients according to genotype in three enzyme gene polymorphisms are shown in Table 1. There was no significant difference in gender, age, duration of illness, current antipsychotic dose, or total AIMS score between subject groups, sorted according to the COMT, MAOA, or MAOB genotype (Table 1). Since males are hemizygous for X chromosome markers, there are only two groups of male subjects for the MAO genes. The results of the analysis of a dichotomous trait in relation to TD diagnosis are shown in Table

2. We could not find any significant allelic association between TD and the enzyme gene polymorphisms. The male COMT, MAOA and MAOB data were grouped into six combinations of functional enzyme expressionyactivity classes (Tables 3 and 4). In the test of additive effects, no significant differences were observed between patients with TD and without TD in compound genotypes, and there was no support for the hypothesis that polymorphisms at COMT and MAOA or MAOB loci combined exerted joint effects on susceptibility to TD wcompound genotype patients with TD vs. without TD (Monte Carlo tests): COMT and MAOA polymorphisms: x2s0.64, d.f.s5, Ps 0.99; COMT and MAOB polymorphisms: x2s 2.78, d.f.s5, Ps0.73x. Moreover, there was no

C. Matsumoto et al. / Psychiatry Research 127 (2004) 1–7 Table 2 Allele frequencies of the three enzyme gene polymorphisms in patients with and without TD With TD (Ns43) With TD (Ns163) x2 COMT H 53 L 33 MAOA Female 2 0 3 22 4 16 5 0 Male 2 0 3 14 4 10 5 0 Total 2 0 3 36 4 26 5 0 MAOB Female A 33 G 5 Male A 20 G 4 Total A 53 G 9

Table 3 Compound male polymorphisms

P

5

genotypes

for

COMT

0.83 0.36 COMT

1 98 62 1

0.62 0.81

1 49 32 0

0.33 1.00

2 147 94 1

0.90 0.88

141 21

–

1.00

69 13

–

1.00

210 34

0.01 0.91

evidence for epistasis between COMT and either MAO gene (Tables 3 and 4). The number of females was too small to perform this analysis given the number of composite genotype permutations.

HyH HyL LyL

Without TD

Allele 3

Allele 4

Allele 3

Allele 4

5 9 1

5 4 1

20 28 3

13 16 5

Compound genotype patients with TD vs. without TD (Monte Carlo test): x2s0.64, d.f.s5, Ps0.99. Epistasis (Monte Carlo tests): with TD: x2s0.96, d.f.s2, Ps0.62; without TD: x2s1.93, d.f.s2, Ps0.38.

et al., 2001), NcoI (Inada et al., 1997), or y141 C InsyDel (Inada et al., 1999; Hori et al., 2001) polymorphisms. Recently, Kaiser et al. (2002) showed no significant association between nine known polymorphisms of DRD2 and TD, or between the haplotypes of these polymorphisms and TD. In the present study, we focused on the relationship between dopamine degradation enzyme genes and TD. COMT catabolizes dopamine by O-methylation and MAOs catabolize it by oxidative deamination (Boulton and Eisenhofer, 1998). Thus, we supposed that these deranged enzyme activities might be related to the susceptibility to develop TD through altered dopaminergic neurotransmission in the central nervous system. We analyzed the relationship between TD and functional polymorphisms of these enzyme genes, namely the Table 4 Compound male polymorphisms

4. Discussion The dopamine hypothesis for TD has led to examination of the association between dopamine D2 receptor (DRD2) gene polymorphisms and TD. Chen et al. (1997) reported a significant association between the TaqI A polymorphism and TD in 83 female patients with schizophrenia. However, subsequent studies have provided no evidence of positive associations between TD and TaqI A (Hori et al., 2001), Ser311Cys (Chong et al., 2003; Hori

MAOA

MAOA With TD

218 108

and

genotypes

for

COMT

and

MAOB

MAOB With TD

COMT

HyH HyL LyL

Without TD

A

G

A

G

7 12 1

3 1 1

27 37 7

6 8 1

Compound genotype patients with TD vs. without TD (Monte Carlo test): x2s2.78, d.f.s5, Ps0.73. Epistasis (Monte Carlo tests): with TD: x2s2.98, d.f.s2, Ps0.23; without TD: x2s0.15, d.f.s2, Ps0.93.

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valineymethionine polymorphism of codon 108y 158 in the COMT gene, the 30-bp repeat polymorphism in the promoter of the MAOA gene, and the AyG polymorphism in intron 13 of the MAOB gene. We could not find differences in the total AIMS score among subjects divided on the basis of the genotypes of each polymorphism in this study. Moreover, there was no difference in the allele frequency of each polymorphism between subjects with and without TD. Furthermore, we did not find any evidence for additive effects of the COMT and MAOA or MAOB genes. Our results provide no evidence of association between TD and these functional polymorphisms and suggest that functional genetic variation in the COMT, MAOA, or MAOB gene, alone or in combination, may not play a major role in the development of TD. Our results are consistent with the previous study by Herken et al. (2003) that analyzed COMT genotypes in the context of TD. In their study, the COMT gene polymorphism was not associated with the susceptibility to TD, which the results of the present study may affirm. The present study, however, does have several limitations. First, although our results were negative, the findings may be restricted to the Japanese population as there may be ethnic differences. Moreover, most of our patients had taken antiparkinsonian drugs andyor benzodiazepines in addition to typical antipsychotic drugs, which are known to influence the occurrence of TD (Shale and Tanner, 1996; Egan et al., 1997; Glazer, 2000). Furthermore, the assessment of other movement disorders such as neuroleptic-induced parkinsonism, which could also mask TD, was not methodically performed in the present study. Finally, our sample size may be small and may not be powerful enough, especially for the analysis of a combination of genotypes, as the cells in the constructed contingency tables of the combinations become many and each cell thus has relatively small counts (Tables 3 and 4). Central dopaminergic neurotransmission can still be subject to genetic control of various other dopamine-regulating enzymes including tyrosine hydroxylase, dopamine b-hydroxylase, and dopamine transporter. These other enzyme genes may

need to be analyzed in relation to the susceptibility to develop TD. Acknowledgments This work was supported by Grant-in-Aid for Young Scientists B, number 13770565, for Science Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors thank Dr Yoshitaro Mine, Dr Akira Eto, Dr Yoshinori Eto, Dr Yasuhiro Tsutsumi, Dr Kenji Yamaura, Dr Toshihiro Yamaura, and Dr Takaharu Hayashida for the referral of patients for this study. References Andreassen, O.A., Jorgensen, H.A., 2000. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats: implications for tardive dyskinesia? Progress in Neurobiology 61, 525–541. Balciuniene, J., Emilsson, L., Oreland, L., Pettersson, U., Jazin, E.E., 2002. Investigation of the functional effect of monoamine oxidase polymorphisms in human brain. Human Genetics 110, 1–7. Boulton, A.A., Eisenhofer, G., 1998. Catecholamine metabolism: from molecular understanding to clinical diagnosis and treatment. Advances in Pharmacology 42, 273–292. Casey, D.E., 2000. Tardive dyskinesia: pathophysiology and animal models. Journal of Clinical Psychiatry 61 (Suppl 4), 5–9. Chakos, M.H., Lieberman, J.A., Bilder, R.M., Borenstein, M., Lerner, G., Bogerts, B., Wu, H., Kinon, B., Ashtari, M., 1994. Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry 151, 1430–1436. Chen, C.H., Wei, F.C., Koong, F.J., Hsiao, K.J., 1997. Association of TaqI A polymorphism of dopamine D2 receptor gene and tardive dyskinesia in schizophrenia. Biological Psychiatry 41, 827–829. Chong, S.A., Tan, E.C., Tan, C.H., Mythily, C.H., Chan, Y.H., 2003. Polymorphisms of dopamine receptors and tardive dyskinesia among Chinese patients with schizophrenia. American Journal of Medical Genetetics 116B, 51–54. Corson, P.W., Nopoulos, P., Miller, D.D., Arndt, S., Andreasen, N.C., 1999. Change in basal ganglia volume over 2 years in patients with schizophrenia: typical vs. atypical neuroleptics. American Journal of Psychiatry 156, 1200–1204. Deckert, J., Catalano, M., Syagailo, Y.V., Bosi, M., Okladnova, ¨ O., Bella, D.D., Nothen, M.M., Maffei, P., Franke, P., Fritze, J., Maier, W., Propping, P., Beckmann, H., Bellodi, L., Lesch, K.P., 1999. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Human Molecular Genetics 8, 621–624.

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