Journal of Molecular Neuroscience

, Volume 64, Issue 3, pp 341–345 | Cite as

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

  • Sadaf Mohtashami
  • Qin He
  • Jennifer A. Ruskey
  • Sirui Zhou
  • Patrick A. Dion
  • Richard P. Allen
  • Christopher J. Earley
  • Edward A. Fon
  • Lan Xiong
  • Nicolas Dupre
  • Yves Dauvilliers
  • Guy A. Rouleau
  • Ziv Gan-Or
Article

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.

Keywords

Restless legs syndrome Parkinson’s disease Genetics TOX3 

Notes

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.

Compliance with Ethical Standards

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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Sadaf Mohtashami
    • 1
    • 2
  • Qin He
    • 3
    • 4
  • Jennifer A. Ruskey
    • 2
    • 5
  • Sirui Zhou
    • 6
  • Patrick A. Dion
    • 2
    • 5
    • 7
  • Richard P. Allen
    • 8
  • Christopher J. Earley
    • 8
  • Edward A. Fon
    • 2
    • 5
  • Lan Xiong
    • 3
    • 4
  • Nicolas Dupre
    • 9
  • Yves Dauvilliers
    • 10
  • Guy A. Rouleau
    • 2
    • 5
    • 7
  • Ziv Gan-Or
    • 2
    • 5
    • 7
  1. 1.Department of Experimental MedicineMcGill UniversityMontrealCanada
  2. 2.Montreal Neurological Institute and Hospital, The Department of Human GeneticsMcGill UniversityMontrealCanada
  3. 3.Laboratoire de neurogénétique, Centre de rechercheInstitut universitaire en santé mentale de MontréalMontrealCanada
  4. 4.Département de psychiatrieUniversité de MontréalMontrealCanada
  5. 5.Department of Neurology and NeurosurgeryMcGill UniversityMontrealCanada
  6. 6.Department of Medicine, Faculty of MedicineUniversité de MontréalMontrealCanada
  7. 7.Department of Human GeneticsMcGill UniversityMontrealCanada
  8. 8.Department of NeurologyThe Johns Hopkins Bayview Medical CenterBaltimoreUSA
  9. 9.Division of Neurosciences, CHU de Québec - Université Laval and the Department of Medicine, Faculty of MedicineLaval UniversityQuebec CityCanada
  10. 10.National Reference Center for Narcolepsy, Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, Inserm U1061University of MontpellierMontpellierFrance

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