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TOX3 Variants Are Involved in Restless Legs Syndrome and Parkinson’s Disease with Opposite Effects

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Abstract

Parkinson’s disease (PD) and restless legs syndrome (RLS) may be clinically and/or etiologically related, yet this association is under debate. Single-nucleotide polymorphisms (SNPs) in the TOX3 gene locus were implicated in both RLS and PD genome-wide association studies (GWASs), suggesting a potential pleiotropy. Two case-control cohorts including 644 PD patients, 457 RLS patients, and 945 controls were genotyped for one known RLS-related SNP (rs3104767) and one PD-related SNP (rs4784226) in the TOX3 locus. The associations between genotype and PD and RLS risk were tested using multivariate regression models. The allele frequencies of RLS-related SNP rs3104767 in RLS patients and controls were 0.35 and 0.43, respectively (OR 0.70, p = 0.0007). Regression model suggested that this association is derived by homozygous carriage of rs3104767 (adjusted p = 0.008). A nominal association was observed for homozygous carriers of the rs3104767 SNP in PD (OR 1.62, 95% CI 1.05–2.54, p = 0.034), i.e., with an opposite direction of effect on RLS and PD, but this was not significant after Bonferroni correction. However, data from published GWASs of RLS and PD, and from the PDgene database, further supported these inverse associations. Our results confirm the association between the TOX3 SNP rs3104767 and RLS and suggest that TOX3 variants are involved in both RLS and PD, but with different or even opposite effects. Studies in larger populations of different ethnicities are required to further refine the TOX3 locus is involved in RLS and PD.

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References

  • Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB, International Restless Legs Syndrome Study Group (2014) Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 15(8):860–873. https://doi.org/10.1016/j.sleep.2014.03.025

    Article  PubMed  Google Scholar 

  • Chang D, Nalls MA, Hallgrimsdottir IB et al (2017) A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet 49(10):1511–1516. https://doi.org/10.1038/ng.3955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54(11 Suppl 5):S21–S23

    CAS  PubMed  Google Scholar 

  • Gan-Or Z, Alcalay RN, Bar-Shira A, Leblond CS, Postuma RB, Ben-Shachar S, Waters C, Johnson A, Levy O, Mirelman A, Gana-Weisz M, Dupré N, Montplaisir J, Giladi N, Fahn S, Xiong L, Dion PA, Orr-Urtreger A, Rouleau GA (2015a) Genetic markers of restless legs syndrome in Parkinson disease. Parkinsonism Relat Disord 21(6):582–585. https://doi.org/10.1016/j.parkreldis.2015.03.010

    Article  PubMed  PubMed Central  Google Scholar 

  • Gan-Or Z, Zhou S, Ambalavanan A, Leblond CS, Xie P, Johnson A, Spiegelman D, Allen RP, Earley CJ, Desautels A, Montplaisir JY, Dion PA, Xiong L, Rouleau GA (2015b) Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome. Sleep Med 16(9):1151–1155. https://doi.org/10.1016/j.sleep.2015.06.002

    Article  PubMed  Google Scholar 

  • Garcia-Borreguero D, Odin P, Serrano C (2003) Restless legs syndrome and PD: a review of the evidence for a possible association. Neurology 61(6 Suppl 3):S49–S55. https://doi.org/10.1212/WNL.61.6_suppl_3.S49

    Article  PubMed  Google Scholar 

  • Lee JE, Shin HW, Kim KS, Sohn YH (2009) Factors contributing to the development of restless legs syndrome in patients with Parkinson disease. Mov Disord 24(4):579–582. https://doi.org/10.1002/mds.22410

    Article  PubMed  Google Scholar 

  • Rijsman RM, Schoolderman LF, Rundervoort RS, Louter M (2014) Restless legs syndrome in Parkinson’s disease. Parkinsonism Relat Disord 20(Suppl 1):S5–S9. https://doi.org/10.1016/S1353-8020(13)70004-X

    Article  PubMed  Google Scholar 

  • Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, Dauvilliers Y, Stefani A, Högl B, Poewe W, Kemlink D, Sonka K, Bachmann CG, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek Z, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Allen RP, Earley CJ, Ondo WG, Xiong L, Montplaisir J, Gan-Or Z, Perola M, Vodicka P, Dina C, Franke A, Tittmann L, Stewart AFR, Shah SH, Gieger C, Peters A, Rouleau GA, Berger K, Oexle K, di Angelantonio E, Hinds DA, Müller-Myhsok B, Winkelmann J, Balkau B, Ducimetière P, Eschwège E, Rancière F, Alhenc-Gelas F, Gallois Y, Girault A, Fumeron F, Marre M, Roussel R, Bonnet F, Bonnefond A, Cauchi S, Froguel P, Cogneau J, Born C, Caces E, Cailleau M, Lantieri O, Moreau JG, Rakotozafy F, Tichet J, Vol S, Agee M, Alipanahi B, Auton A, Bell RK, Bryc K, Elson SL, Fontanillas P, Furlotte NA, Hinds DA, Hromatka BS, Huber KE, Kleinman A, Litterman NK, McIntyre MH, Mountain JL, Northover CAM, Pitts SJ, Sathirapongsasuti JF, Sazonova OV, Shelton JF, Shringarpure S, Tian C, Tung JY, Vacic V, Wilson CH (2017) Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol 16(11):898–907. https://doi.org/10.1016/S1474-4422(17)30327-7

    Article  PubMed  PubMed Central  Google Scholar 

  • Seksenyan A, Kadavallore A, Walts AE, de la Torre B, Berel D, Strom SP, Aliahmad P, Funari VA, Kaye J (2015) TOX3 is expressed in mammary ER(+) epithelial cells and regulates ER target genes in luminal breast cancer. BMC Cancer 15(1):22. https://doi.org/10.1186/s12885-015-1018-2

    Article  PubMed  PubMed Central  Google Scholar 

  • Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, Trenkwalder C, Dauvilliers Y, Polo O, Högl B, Berger K, Fuhs A, Gross N, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Xiong L, Montplaisir J, Rouleau GA, Fietze I, Vávrová J, Kemlink D, Sonka K, Nevsimalova S, Lin SC, Wszolek Z, Vilariño-Güell C, Farrer MJ, Gschliesser V, Frauscher B, Falkenstetter T, Poewe W, Allen RP, Earley CJ, Ondo WG, Le WD, Spieler D, Kaffe M, Zimprich A, Kettunen J, Perola M, Silander K, Cournu-Rebeix I, Francavilla M, Fontenille C, Fontaine B, Vodicka P, Prokisch H, Lichtner P, Peppard P, Faraco J, Mignot E, Gieger C, Illig T, Wichmann HE, Müller-Myhsok B, Meitinger T (2011) Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genet 7(7):e1002171. https://doi.org/10.1371/journal.pgen.1002171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh P, Walters AS, Tsuang JW (2012) Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath 16(4):987–1007. https://doi.org/10.1007/s11325-011-0606-x

    Article  PubMed  Google Scholar 

  • Yuan SH, Qiu Z, Ghosh A (2009) TOX3 regulates calcium-dependent transcription in neurons. Proc Natl Acad Sci U S A 106(8):2909–2914. https://doi.org/10.1073/pnas.0805555106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the patients and controls for their participation in the study. We thank Daniel Rochefort, Pascale Hince, Helene Catoire, Cynthia Bourassa, Pierre Provencher, Cathy Mirarchi, and Vessela Zaharieva for their assistance. We thank Drs M. Charif and C. Geny for the recruitment of PD patients in France. We thank the Quebec Parkinson’s Network and its members (http://rpq-qpn.ca/) for their collaboration.

Funding

This work was financially supported by the Michael J. Fox Foundation and the Canadian Consortium on Neurodegeneration in Aging (CCNA). SM was supported by the Canadian Institutes of Health Research (CIHR) Master’s Award. GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.

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Authors and Affiliations

  1. Department of Experimental Medicine, McGill University, Montreal, Québec, Canada

    Sadaf Mohtashami

  2. Montreal Neurological Institute and Hospital, The Department of Human Genetics, McGill University, 1033 Pine Avenue West, Ludmer Pavilion, room 312, Montreal, QC, H3A 1A1, Canada

    Sadaf Mohtashami, Jennifer A. Ruskey, Patrick A. Dion, Edward A. Fon, Guy A. Rouleau & Ziv Gan-Or

  3. Laboratoire de neurogénétique, Centre de recherche, Institut universitaire en santé mentale de Montréal, Montreal, Québec, Canada

    Qin He & Lan Xiong

  4. Département de psychiatrie, Université de Montréal, Montreal, Québec, Canada

    Qin He & Lan Xiong

  5. Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada

    Jennifer A. Ruskey, Patrick A. Dion, Edward A. Fon, Guy A. Rouleau & Ziv Gan-Or

  6. Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Québec, Canada

    Sirui Zhou

  7. Department of Human Genetics, McGill University, Montreal, Québec, Canada

    Patrick A. Dion, Guy A. Rouleau & Ziv Gan-Or

  8. Department of Neurology, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA

    Richard P. Allen & Christopher J. Earley

  9. Division of Neurosciences, CHU de Québec - Université Laval and the Department of Medicine, Faculty of Medicine, Laval University, Quebec City, Canada

    Nicolas Dupre

  10. National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, Inserm U1061, University of Montpellier, Montpellier, France

    Yves Dauvilliers

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  1. Sadaf Mohtashami
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  2. Qin He
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  3. Jennifer A. Ruskey
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  4. Sirui Zhou
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  5. Patrick A. Dion
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  6. Richard P. Allen
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  8. Edward A. Fon
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  9. Lan Xiong
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  10. Nicolas Dupre
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  11. Yves Dauvilliers
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  12. Guy A. Rouleau
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  13. Ziv Gan-Or
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Corresponding author

Correspondence to Ziv Gan-Or.

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All participants in both PD and RLS cohorts signed informed consent at enrollment, and the study protocols were approved by the institutional ethics review boards.

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Mohtashami, S., He, Q., Ruskey, J.A. et al. TOX3 Variants Are Involved in Restless Legs Syndrome and Parkinson’s Disease with Opposite Effects. J Mol Neurosci 64, 341–345 (2018). https://doi.org/10.1007/s12031-018-1031-4

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  • DOI: https://doi.org/10.1007/s12031-018-1031-4

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