Korean J Schizophr Res.  2013 Oct;16(2):93-97. 10.16946/kjsr.2013.16.2.93.

Association between Antipsychotic-Related Restless Legs Syndrome and the RORA Gene Polymorphism in Schizophrenia

• Jung JS
• Cho CH
• Yoon HK
• Kang SG
• Park YM
• Lee HJ
• Kim L

• KMID: 2288329
• DOI: http://doi.org/10.16946/kjsr.2013.16.2.93

Abstract

OBJECTIVES
The previous studies have suggested genetic vulnerability to restless legs syndrome (RLS) development. The occurrence of antipsychotic-related RLS could also be attributable to differences in genetic susceptibility. This study aimed to investigate whether Retinoid-related orphan receptor A (RORA) gene polymorphism is associated with antipsychotic-related RLS in schizophrenia.
METHODS
We assessed symptoms of antipsychotic-induced RLS in 190 Korean schizophrenic patients and divided the subjects into two groups according to the International Restless Legs Syndrome Study Group diagnostic criteria : 1) subjects that met all of the criteria (n=44) and 2) the remaining subjects who were not considered to be RLS patients (n=146). Single-nucleotide polymorphism in the RORA gene was genotyped by PCR in 190 individuals. The chi2-test was conducted to compare differences between two groups.
RESULTS
The frequencies of genotype (chi2=0.066, p=0.968) of the RORA gene (rs11071547) did not differ significantly between schizophrenic patients with and without RLS. The difference of allele frequencies (chi2=0.008, p=0.927) of the RORA gene (rs 11071547) between the schizophrenic patients with and without RLS were not significant.
CONCLUSION
These results suggest that RORA gene polymorphism does not play a major role in susceptibility to antipsychotic-related RLS in schizophrenia.

Keyword

RLS; Schizophrenia; RORA; Genetic polymorphism; Circadian rhythm

MeSH Terms

Child
Child, Orphaned
Circadian Rhythm
Gene Frequency
Genetic Predisposition to Disease
Genotype
Humans
Polymerase Chain Reaction
Polymorphism, Genetic
Restless Legs Syndrome*
Schizophrenia*

Reference

1). Karroum E, Konofal E, Arnulf I. Restless-legs syndrome. Rev Neurol (Paris). 2008; 164:701–721.

2). Rasmussen J, Videbech P. Restless legs syndrome and depression. Ugeskr Laeger. 2011; 173:2113–2117.

3). Kim WH, Kim BS, Kim SK, Chang SM, Lee DW, Cho MJ, et al. Restless legs syndrome in older people: a community-based study on its prevalence and association with major depressive disorder in older Korean adults. Int J Geriatr Psychiatry. 2012; 27:565–572.

4). Winter AC, Schurks M, Glynn RJ, Buring JE, Gaziano JM, Berger K, et al. Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. BMJ Open. 2012; 2:e000866.

5). Cho YW, Shin WC, Yun CH, Hong SB, Kim JH, Allen RP, et al. Epidemiology of restless legs syndrome in Korean adults. Sleep. 2008; 31:219–223.

6). Trotti LM, Rye DB. Restless legs syndrome. Handb Clin Neurol. 2011; 100:661–673.

7). Giguere V, Tini M, Flock G, Ong E, Evans RM, Otulakowski G. Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev. 1994; 8:538–553.

8). Gachon F, Nagoshi E, Brown SA, Ripperger J, Schibler U. The mammalian circadian timing system: from gene expression to physiology. Chromosoma. 2004; 113:103–112.

9). DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci. 2007; 10:543–545.

10). Guillaumond F, Dardente H, Giguere V, Cermakian N. Differential control of Bmal1 circadian transcription by REV-ERB and ROR nuclear receptors. J Biol Rhythms. 2005; 20:391–403.

11). Sato TK, Panda S, Miraglia LJ, Reyes TM, Rudic RD, McNamara P, et al. A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron. 2004; 43:527–537.

12). Solt LA, Kojetin DJ, Burris TP. The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med Chem. 2011; 3:623–638.

13). Champion D, Pathirana S, Flynn C, Taylor A, Hopper JL, Berkovic SF, et al. Growing pains: Twin family study evidence for genetic susceptibility and a genetic relationship with restless legs syndrome. Eur J Pain. 2012.

14). Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Rouleau GA. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. Am J Hum Genet. 2001; 69:1266–1270.

15). Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain. 2003; 126:1485–1492.

16). Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet. 2004; 74:876–885.

17). Levchenko A, Provost S, Montplaisir JY, Xiong L, St-Onge J, Thi-bodeau P, et al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology. 2006; 67:900–901.

18). Pichler I, Marroni F, Volpato CB, Gusella JF, Klein C, Casari G, et 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; 79:716–723.

19). Kemlink D, Plazzi G, Vetrugno R, Provini F, Polo O, Stiasny-Kol-ster K, et al. Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13. Neurogenetics. 2008; 9:75–82.

20). Levchenko A, Montplaisir JY, Asselin G, Provost S, Girard SL, Xiong L, et al. Autosomal-dominant locus for Restless Legs Syndrome in French-Canadians on chromosome 16p12.1. Mov Disord. 2009; 24:40–50.

21). Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirs-son TE, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007; 357:639–647.

22). Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilza-deh S, et al. Genomewide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007; 39:1000–1006.

23). Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet. 2008; 40:946–948.

24). Kang SG, Lee HJ, Jung SW, Cho SN, Han C, Kim YK, et al. Characteristics and clinical correlates of restless legs syndrome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31:1078–1083.

25). Kang SG, Lee HJ, Kim L. Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine. J Psychopharmacol. 2009; 23:597–601.

26). Kang SG, Lee HJ, Choi JE, Park JH, Lee SS, Han CS, et al. Possible association between G-protein β3 subunit C825T polymorphism and antipsychotic-induced restless legs syndrome in schizophrenia. Acta Neuropsychiatrica. 2007; 19:351–356.

27). Kang SG, Lee HJ, Choi JE, Park YM, Park JH, Han C, et al. Association study between antipsychotics- induced restless legs syndrome and polymorphisms of dopamine D1, D2, D3, and D4 receptor genes in schizophrenia. Neuropsychobiology. 2008; 57:49–54.

28). Cho CH, Kang SG, Choi JE, Park YM, Lee HJ, Kim L. Association between Antipsychotics-Induced Restless Legs Syndrome and Tyrosine Hydroxylase Gene Polymorphism. Psychiatry Investig. 2009; 6:211–215.

29). Kang SG, Park YM, Choi JE, Lim SW, Lee HJ, Lee SH, et al. Association study between antipsychotic-induced restless legs syndrome and polymorphisms of monoamine oxidase genes in schizophrenia. Hum Psychopharmacol. 2010; 25:397–403.

30). Kang SG, Lee HJ, Park YM, Yang HJ, Song HM, Lee YJ, et al. The BTBD9 gene may be associated with antipsychotic-induced restless legs syndrome in schizophrenia. Hum Psychopharmacol. 2013; 28:117–123.

31). Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003; 4:121–132.

32). Soldatos CR, Dikeos DG, Paparrigopoulos TJ. The diagnostic validity of the Athens Insomnia Scale. J Psychosom Res. 2003; 55:263–267.

33). Lykke J, Hesse M, Austin SF, Oestrich I. Validity of the BPRS, the BDI and the BAI in dual diagnosis patients. Addict Behav. 2008; 33:292–300.

34). Michaud M, Dumont M, Selmaoui B, Paquet J, Fantini ML, Montplaisir J. Circadian rhythm of restless legs syndrome: relationship with biological markers. Ann Neurol. 2004; 55:372–380.

35). Odrcich M, Bailey JM, Cahill CM, Gilron I. Chronobiological characteristics of painful diabetic neuropathy and postherpetic neuralgia: diurnal pain variation and effects of analgesic therapy. Pain. 2006; 120:207–212.

36). Baier PC, Trenkwalder C. Circadian variation in restless legs syndrome. Sleep Med. 2007; 8:645–650.

37). Akashi M, Takumi T. The orphan nuclear receptor RORalpha reg-ulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol. 2005; 12:441–448.

38). Kamphuis W, Cailotto C, Dijk F, Bergen A, Buijs RM. Circadian expression of clock genes and clock-controlled genes in the rat retina. Biochem Biophys Res Commun. 2005; 330:18–26.

39). Tosini G, Davidson AJ, Fukuhara C, Kasamatsu M, Castanon-Cervantes O. Localization of a circadian clock in mammalian photore-ceptors. FASEB J. 2007; 21:3866–3871.

40). Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M, et al. Nuclear receptor expression links the circadian clock to metabolism. Cell. 2006; 126:801–810.

41). Ueda HR, Chen W, Adachi A, Wakamatsu H, Hayashi S, Takasugi T, et al. A transcription factor response element for gene expression during circadian night. Nature. 2002; 418:534–539.

42). Ino H. Immunohistochemical characterization of the orphan nuclear receptor ROR alpha in the mouse nervous system. J Histochem Cytochem. 2004; 52:311–323.

43). Boukhtouche F, Vodjdani G, Jarvis CI, Bakouche J, Staels B, Mallet J, et al. Human retinoic acid receptor-related orphan receptor al-pha1 overexpression protects neurones against oxidative stress-induced apoptosis. J Neurochem. 2006; 96:1778–1789.

44). Frederic F, Chianale C, Oliver C, Mariani J. Enhanced endocrine response to novel environment stress and lack of corticosterone circadian rhythm in staggerer (Rora sg/sg) mutant mice. J Neurosci Res. 2006; 83:1525–1532.

45). Jarvis CI, Staels B, Brugg B, Lemaigre-Dubreuil Y, Tedgui A, Mariani J. Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor's role beyond the cerebellum. Mol Cell Endocrinol. 2002; 186:1–5.

46). Dzhagalov I, Giguere V, He YW. Lymphocyte development and function in the absence of retinoic acid-related orphan receptor alpha. J Immunol. 2004; 173:2952–2959.

47). Kopmels B, Mariani J, Delhaye-Bouchaud N, Audibert F, Fradelizi D, Wollman EE. Evidence for a hyperexcitability state of staggerer mutant mice macrophages. J Neurochem. 1992; 58:192–199.

48). Kripke DF, Nievergelt CM, Tranah GJ, Murray SS, Rex KM, Grizas AP, et al. FMR1, circadian genes and depression: suggestive associations or false discovery? J Circadian Rhythms. 2013; 11:3.

49). Lavebratt C, Sjoholm LK, Partonen T, Schalling M, Forsell Y. PER2 variantion is associated with depression vulnerability. Am J Med Genet B Neuropsychiatr Genet. 2010; 153:570–581.

50). Utge SJ, Soronen P, Loukola A, Kronholm E, Ollila HM, Pirkola S, et al. Systematic analysis of circadian genes in a population-based sample reveals association of TIMELESS with depression and sleep disturbance. PLoS One. 2010; 5:e9259.

51). Kripke DF, Shadan FF, Dawson A, Cronin JW, Jamil SM, Grizas AP, et al. Genotyping sleep disorders patients. Psychiatry Investig. 2010; 7:36–42.