Dopamine beta-hydroxylase gene polymorphisms and psychotic symptoms in schizophrenia.код для вставкиСкачать
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: email@example.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.  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.  reported a significant decrease in the serum DBH activity in patients with psychotic major depressive disorder compared to controls. Cubells et al.  suggested that a specific haplotype associated with low plasma DBH activity was associated with greater vulnerability to cocaine-induced paranoia. Yamamoto et al.  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.  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 Cubells JF, Zabetian CP. 2004. Human genetics of plasma dopamine b-hydroxylase activity: Applications to research in psychiatry and neurology. Psychopharmacology 174:463–476. Cubells JF, Kranzler HR, McCance-Katz E, Anderson GM, Malison RT, Price LH, Gelernter J. 2000. A haplotype at the DBH locus, associated Williams HJ, Bray N, Murphy KC, Cardno AG, Jones LA, Owen MJ. 1999. No evidence for association between schizophrenia and a functional variant of the human dopamine beta-hydroxylase gene (DBH). Am J Med Genet 88:557–559. Wood JG, Joyce PR, Miller AL, Mulder RT, Kennedy MA. 2002. A polymorphism in the dopamine b-hydroxylase gene is associated with ‘‘paranoid ideation’’ in patients with major depression. Biol Psychiatry 51:365–369. Yamamoto K, Cubells JF, Gelernter J, Benkelfat C, Lalonde P, Bloom D, Lal S, Labelle A, Turecki F, Rouleau GA, Joober R. 2003. Dopamine betahydroxylase (DBH) gene and schizophrenia phenotypic variability: A genetic association study. Am J Med Genet (Neuropsychiatr Genet) 117B:33–38.