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Possible association between G-protein β3 subunit C825T polymorphism and antipsychotic-induced restless legs syndrome in schizophrenia

  • Seung-Gul Kang (a1), Heon-Jeong Lee (a1) (a2), Jung-Eun Choi (a1) (a2), Jae-Hong Park (a3), Sang-Shin Lee (a3), Changsu Han (a1), Yong-Ku Kim (a1), Seung-Hyun Kim (a1), Min-Soo Lee (a1), Sook-Haeng Joe (a1), In-Kwa Jung (a1) and Leen Kim (a1)...



The incidence of restless legs syndrome (RLS) is presumed to be higher among people with schizophrenia who take antipsychotic medication, most of which blocks the dopamine D2 receptor. The purpose of this study was to determine whether the G-protein β3 subunit (GNB3) C825T polymorphism is associated with antipsychotic-induced RLS in schizophrenia.


We examined 178 Korean patients with schizophrenia. All of the subjects were evaluated using the diagnostic criteria of the International Restless Legs Syndrome Study Group and the International Restless Legs Scale. Genotyping was performed for the C825T polymorphism in the GNB3 gene.


The genotype distribution did not differ significantly between antipsychotic-induced RLS patients and patients who had no-RLS symptoms (χ2 = 4.30, p = 0.116). The genotypes of the C825T single-nucleotide polymorphism (SNP) were classified into two groups: C+ (CC and CT genotypes) and C– (TT genotype). The presence of the C allele (C+) was associated with an increased likelihood of RLS (χ2 = 4.14, p = 0.042; odds ratio = 2.56, 95% confidence interval = 1.02–6.47).


These results suggest that the GNB3 C825T SNP is associated with RLS in schizophrenia. However, confirming this association requires future larger scale studies in which the effects of medication are strictly controlled.


Corresponding author

Heon-Jeong Lee, Department of Psychiatry, Anam Hospital, Korea University College of Medicine, Anam-dong 5-ga, Seongbuk-gu, Seoul 136-705, Korea. Tel: +82 2 9205815; Fax: +82 2 9297679; E-mail:


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1.Kryger, MH, Roth, T, Dement, WC. Principles and practice of sleep medicine, 4th edn. Philadelphia: Elsevier Saunders, 2005.
2.Richard, BB. Sleep medicine pearls, 2nd edn. Philadelphia: Mosby, 2003.
3.Montplaisir, J, Boucher, S, Poirier, G, Lavigne, G, Lapierre, O, Lesperance, P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997;12:6165.
4.Ondo, W, Jankovic, J. Restless legs syndrome: clinicoetiologic correlates. Neurology 1996;47:14351441.
5.Walters, AS, Hickey, K, Maltzman, Jet al. A questionnaire study of 138 patients with restless legs syndrome: the ‘Night-Walkers’ survey. Neurology 1996;46:9295.
6.Ondo, WG, Vuong, KD, Wang, Q. Restless legs syndrome in monozygotic twins: clinical correlates. Neurology 2000;55:14041406.
7.Desautels, A, Turecki, G, Montplaisir, J, Sequeira, A, Verner, A, Rouleau, G. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12 q. Am J Hum Genet 2001;69:12661270.
8.Desautels, A, Turecki, G, Montplaisir, Jet al. Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity. Arch Neurol 2005;62:591596.
9.Bonati, MT, Ferini-Strambi, L, Aridon, P, Oldani, A, Zucconi, M, Casari, G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 2003;126:14851492.
10.Levchenko, A, Montplaisir, JY, Dube, MPet al. The 14q restless legs syndrome locus in the French Canadian population. Ann Neurol 2004;55:887891.
11.Chen, S, Ondo, WG, Rao, S, Li, L, Chen, Q, Wang, Q. Genomewide linkage scan identifies a novel susceptibility locus for RLS on chromosome 9p. Am J Hum Genet 2004;74:876889.
12.Pichler, I, Marroni, F, Volpato, CBet al. Linkage analysis identifies a novel locus for restless legs syndrome on chromosome 2q in a South Tyrolean population isolate. Am J Hum Genet 2006;79:716723.
13.Levchenko, A, Provost, S, Montplaisir, JYet al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology 2006;67:900901.
14.Kang, SG, Lee, HJ, Jung, SWet al. Characteristics and clinical correlates of restless legs syndrome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:10781083.
15.Foord, SM, Bonner, TI, Neubig, RRet al. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev 2005;57:279288.
16.Hamm, HE. The many faces of G protein signalling. J Biol Chem 1998;273:669672.
17.Benjafield, AV, Jeyasingam, CL, Nyholt, DR, Griffiths, LR, Morris, BJ. G-protein beta3 subunit gene (GNB3) variant in causation of essential hypertension. Hypertension 1998;32:10941097.
18.Hegele, RA, Anderson, C, Young, TK, Connelly, PW. G-protein beta3 subunit gene splice variant and body fat distribution in Nunavut Inuit. Genome Res 1999;9:972977.
19.Lee, HJ, Cha, JH, Ham, BJet al. Association between a G-protein beta 3 subunit gene polymorphism and the symptomatology and treatment responses of major depressive disorders. Pharmacogenomics J 2004;4:2933.
20.Lee, HJ, Sung, SM, Han, CSet al. G-protein beta3 subunit C825T polymorphism tends to be associated with seasonal variation in young male college students. Neuropsychobiology 2005;52:135139.
21.Műller, DJ, De Luca, V, Sicard, Tet al. Suggestive association between the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) and clinical improvement with antipsychotics in schizophrenia. Eur Neuropsychopharmacol 2005;15:525531.
22.Siffert, W, Forster, P, Jockel, KHet al. Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol 1999;10:19211930.
23.Siffert, W, Rosskopf, D, Siffert, Get al. Association of a human G-protein beta 3 subunit variant with hypertension. Nat Genet 1998;18:4548.
24.Tsai, SJ, Yu, YW, Lin, CH, Wang, YC, Chen, JY, Hong, CJ. Association study of adrenergic beta3 receptor (Trp64Arg) and G-protein beta3 subunit gene (C825T) polymorphisms and weight change during clozapine treatment. Neuropsychobiology 2004;50:3740.
25.Zill, P, Baghai, TC, Zwanzger, Pet al. Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment. Neuroreport 2000;11:18931897.
26.Avissar, S, Roitman, G, Schreiber, G. Differential effects of the antipsychotics haloperidol and clozapine on G protein measures in mononuclear leukocytes of patients with schizophrenia. Cell Mol Neurobiol 2001;21:799811.
27.Kovoor, A, Seyffarth, P, Ebert, Jet al. D2 dopamine receptors colocalize regulator of G-protein signalling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways. J Neurosci 2005;25:21572165.
28.Sheu, SY, Handke, S, Brocker-Preuss, Met al. The C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. J Pathol 2007;211:6066.
29.American Psychiatric Association. Diagnostic and statistical manual of mental disorders: DSM-IV. Washington, DC: American Psychiatric Association, 1994.
30.Han, OS, Hong, JP. Structured clinical interview for DSM-IV axis I disorder-Korean version. Seoul: Hana Medical Publishing, 2000.
31.Allen, RP, Picchietti, D, Hening, WA, Trenkwalder, C, Walters, AS, Montplaisi, J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless leg syndrome diagnosis and epidemiology workshop at the National Institute of Health. Sleep Med 2003;4:101119.
32.Walters, AS, Lebrocq, C, Dhar, Aet al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121132.
33.Wunderlich, GR, Evans, KR, Sills, Tet al. An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome. Sleep Med 2005;6:131139.
34.Overall, JE, Gorham, DR. The brief psychiatric rating scale. Psychol Rep 1962;10:799812.
35.Serretti, A, Lorenzi, C, Cusin, Cet al. SSRIs antidepressant activity is influenced by G beta 3 variants. Eur Neuropsychopharmacol 2003;13:117122.
36.Hauge Opdal, S, Melien, O, Rootwelt, H, Vege, A, Arnestad, M, Ole Rognum, T. The G protein beta3 subunit 825C allele is associated with sudden infant death due to infection. Acta Paediatr 2006;95:11291132.
37.Desautels, A, Turecki, G, Montplaisir, Jet al. Dopaminergic neurotransmission and restless legs syndrome: a genetic association analysis. Neurology 2001;57:13041306.
38.Desautels, A, Turecki, G, Montplaisir, Jet al. Evidence for a genetic association between monoamine oxidase A and restless legs syndrome. Neurology 2002;59:215219.
39.Kim, JW. Association study and the population admixture. In: Korean Society of Biological Psychiatry, ed. Human Neurobehavioral Genetics in the 21st Century-Winter Workshop. Seoul: Korean Society of Biological Psychiatry, 2003: 9398.
40.Borgwardt, SJ, Fusar-Poli, P. Imaging genomics – an integrative approach to understand the biological susceptibility for schizophrenia. Med hypotheses 2007;68:1426.
41.Tracy, DK, Shergill, SS. Imaging auditory hallucinations in schizophrenia. Acta Neuropsychiatr 2006;18:7178.
42.Malhi, GS, Lagopoulos, J. Neuroimaging in neuropsychiatric disorders. Acta Neuropsychiatr 2006;18:5960.



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