Hostname: page-component-848d4c4894-m9kch Total loading time: 0 Render date: 2024-06-02T11:17:17.828Z Has data issue: false hasContentIssue false
  • English
  • Français

Genetic Association Studies in Restless Legs Syndrome: Risk Variants & Ethnic Differences

Published online by Cambridge University Press:  25 January 2024

Brendan Jen-Wei Tan ,
Xin-Ler Pang ,
Sarah Png ,
Zhi Dong Zhou  and
Eng-King Tan Open the ORCID record for Eng-King Tan [Opens in a new window]
Brendan Jen-Wei Tan
Affiliation:
Department of Neurology, National Neuroscience Institute, Singapore, Singapore
Xin-Ler Pang
Affiliation:
Department of Neurology, National Neuroscience Institute, Singapore, Singapore
Sarah Png
Affiliation:
Department of Neurology, National Neuroscience Institute, Singapore, Singapore
Zhi Dong Zhou
Affiliation:
Department of Neurology, National Neuroscience Institute, Singapore, Singapore The Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
Eng-King Tan*
Affiliation:
Department of Neurology, National Neuroscience Institute, Singapore, Singapore The Neuroscience and Behavioural Disorders Programme, Duke-NUS Medical School, Singapore, Singapore
*
Corresponding author: E.-K. Tan; Email: ekl2ekl2@gmail.com
Get access Rights & Permissions [Opens in a new window]

Abstract:

Background:

Genetic association studies have not produced consistent results in restless legs syndrome (RLS).

Objectives:

To conduct a systematic review on genetic association studies in RLS to highlight the common gene variants and ethnic differences.

Methodology:

We conducted Pubmed, Embase, and Cochrane search using terms “Genetic association studies” and “restless legs syndrome” for candidate gene-based studies. Out of the initial 43 studies, 18 case control studies (from 2012 to 2022) were included. Thirteen studies including 10794 Caucasian subjects (4984 RLS cases and 5810 controls) and five studies involving 2009 Asian subjects (796 RLS cases and 1213 controls) were tabulated and analyzed. In addition, three Genome-Wide Association Studies (GWAS) in Asians and Europeans/Caucasians were included for comparisons.

Results:

In the Asian population, gene variants in BST1, SNCA Rep1, IL1B, BTBD9, and MAP2K5/SKOR1 increased the risk of RLS (odds ratio range 1.2–2.8). In Caucasian populations, examples of variants that were associated with an increased risk of RLS (odds ratio range 1.1–1.9) include those in GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1, and SETBP1. Based on the meta-analysis of GWAS studies, the rs9390170 variant in UTRN gene was identified to be a novel genetic marker for RLS in Asian cohorts, whereas rs113851554 in MEIS1 gene was a strong genetic factor among the >20 identified gene variants for RLS in Caucasian populations.

Conclusion:

Our systemic review demonstrates that multiple genetic variants modulate risk of RLS in Caucasians (such as MEIS1 BTBD9, MAP2K5) and in Asians (such as BTBD9, MAP2K5, and UTRN).

Résumé:

RÉSUMÉ:

Études d’associations génétiques dans le cadre du syndrome des jambes sans repos : variants à risque et différences ethniques.

Contexte :

À ce jour, les études d’associations génétiques n’ont pas permis d’obtenir des résultats cohérents en ce qui regarde le syndrome des jambes sans repos (SJSR).

Objectifs :

Réaliser une analyse systématique des études d’associations génétiques liées au SJSR afin de mettre en évidence des variants génétiques communs ainsi que des différences ethniques.

Méthodologie :

Nous avons donc effectué une recherche sur PubMed, Embase et Cochrane en utilisant les termes « études d’associations génétiques » et « syndrome des jambes sans repos » pour identifier des études basées sur des gènes candidats. Sur 43 études initialement identifiées, 18 études cas témoins menées de 2012 à 2022 ont été incluses à des fins de compilation et d’analyse ; de ce nombre, 13 études incluaient 10 794 sujets caucasiens (4984 cas de SJSR et 5810 témoins) et 5 études incluaient 2009 sujets asiatiques (796 cas de SJSR et 1213 témoins). En outre, trois études d’associations pangénomiques chez des sujets d’origine asiatique et européenne (ou caucasienne) ont été incluses à des fins de comparaison.

Résultats :

Dans la population asiatique, les variants des gènes BST1, SNCA Rep1, IL1B, BTBD9 et MAP2K5/SKOR1 augmentent le risque de SJSR (rapport de cotes de 1,2 à 2,8). Dans les populations caucasiennes, les variants associés à un risque accru de SJSR (rapport de cotes de 1,1 à 1,9) comprennent les gènes GABRR3 TOX3, ADH1B, HMOX1, GLO1, DCDC2C, BTBD9, SKOR1 et SETBP1. Sur la base d’une méta-analyse des études d’associations pangénomiques, le variant rs9390170 du gène UTRN a été identifié comme un nouveau marqueur génétique du SJSR au sein des cohortes asiatiques, tandis que le variant rs113851554 du gène MEIS1 s’est avéré un facteur génétique important parmi les >20 variants génétiques identifiés pour le SJSR au sein des populations caucasiennes.

Conclusion :

Notre analyse systémique démontre en somme que de multiples variants génétiques modulent le risque de SJSR chez des sujets d’origine caucasienne (comme MEIS1, BTBD9, MAP2K5) et chez des sujets d’origine asiatique (comme BTBD9, MAP2K5 et UTRN).

Keywords

Restless legs syndromeRaceEthnicVariants
Type
Original Article
Information
Canadian Journal of Neurological Sciences , First View , pp. 1 - 16
Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of Canadian Neurological Sciences Federation

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Tan, EK, Ondo, W. Restless legs syndrome: clinical features and treatment. Am J Med Sci. 2000;319:397–403.CrossRefGoogle Scholar
Silber, MH, Buchfuhrer, MJ, Earley, CJ, et al. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc. 2021;96:1921–37.CrossRefGoogle ScholarPubMed
Tan, EK, Seah, A, See, SJ, Lim, E, Wong, MC, Koh, KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord. 2001;16:577–9.CrossRefGoogle Scholar
Kim, TJ, Yoon, JE, Park, JA, et al. Prevalence and characteristics of restless legs syndrome in Korean adults: a study in two independent samples of the general population. Neuroepidemiology. 2019;52:193–204.CrossRefGoogle ScholarPubMed
Winkelmann, JSchormair B, Xiong, L, Dion, PA, Rye, DB, Rouleau, GA. Genetics of restless legs syndrome. Sleep Medicine. 2017;31:18–22.CrossRefGoogle ScholarPubMed
Allen, RP, La Buda, MC, Becker, P, Earley, CJ. Family history study of the restless legs syndrome. Sleep Med. 2002;3:S3–S7.CrossRefGoogle ScholarPubMed
Winkelmann, J, Schormair, B, Lichtner, P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39:1000–6.CrossRefGoogle ScholarPubMed
Li, G, Tang, H, Wang, C, et al. Association of BTBD9 and MAP2K5/SKOR1 with restless legs syndrome in Chinese population. Sleep. 2017;40(4). DOI: 10.1093/sleep/zsx028.Google Scholar
Akçimen, F, Ross, JP, Sarayloo, F, et al. Genetic and epidemiological characterization of restless legs syndrome in Québec. Sleep. 2020;43:zsz265. DOI: 10.1093/sleep/zsz265.CrossRefGoogle ScholarPubMed
Huang, Y, Wang, P, Luo, Q, Ma, J. Association of BST1 polymorphism with idiopathic restless legs syndrome in Chinese population. Sleep Breath. 2021;25:1987–93.CrossRefGoogle ScholarPubMed
Zhu, XY, Wang, HM, Wu, TT, et al. SNCA-Rep1 polymorphism correlates with susceptibility and iron deficiency in restless legs syndrome. Parkinsonism Relat Disord. 2020;81:12–7.CrossRefGoogle ScholarPubMed
Chen, J, Luo, Q, Li, G, Huang, Y, Ma, J. Genetic association study of restless legs syndrome in Chinese population. Eur Neurol. 2019;81:47–55.CrossRefGoogle ScholarPubMed
Seo, JE, Yeom, JW, Jeon, S, Cho, CH, Jeong, S, Lee, HJ. Association between CLOCK gene variants and restless legs syndrome in Koreans. Psychiatry Investig. 2021;18:1125–30.CrossRefGoogle ScholarPubMed
Jiménez-Jiménez, FJ, Esguevillas, G, Alonso-Navarro, H, et al. Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome. Pharmacogenomics J. 2018;18:565–77.CrossRefGoogle ScholarPubMed
Mohtashami, S, He, Q, Ruskey, JA, et al. TOX3 variants are involved in restless legs syndrome and Parkinson’s disease with opposite effects. J Mol Neurosci. 2018;64:341–5.CrossRefGoogle ScholarPubMed
Jiménez-Jiménez, FJ, Gómez-Tabales, J, Alonso-Navarro, H, et al. Association between the rs1229984 polymorphism in the alcohol dehydrogenase 1B gene and risk for restless legs syndrome. Sleep. 2017;40(12). https://doi.org/10.1093/sleep/zsx174.CrossRefGoogle ScholarPubMed
Gan-Or, Z, Zhou, S, Ambalavanan, A, et al. Analysis of functional GLO1 variants in the BTBD9 locus and restless legs syndrome. Sleep Med. 2015;16:1151–5.CrossRefGoogle ScholarPubMed
García-Martín, E, Jiménez-Jiménez, FJ, Alonso-Navarro, H, et al. Heme oxygenase-1 and 2 common genetic variants and risk for restless legs syndrome. Medicine (Baltimore). 2015;94:e1448.CrossRefGoogle ScholarPubMed
Jiménez-Jiménez, FJ, Agúndez, BG, Gómez-Tabales, J, et al. Common endothelial nitric oxide synthase single nucleotide polymorphisms are not related with the risk for restless legs syndrome. Front Pharmacol. 2021;12:618989.CrossRefGoogle Scholar
Jiménez-Jiménez, FJ, García-Martín, E, Alonso-Navarro, H, et al. Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl-transferase (HNMT) gene and risk for restless legs syndrome. J Neural Transm (Vienna). 2017;124:285–91.CrossRefGoogle ScholarPubMed
Gan-Or, Z, Zhou, S, Johnson, A, et al. Case-control and family-based association study of specific PTPRD variants in restless legs syndrome. Mov Disord Clin Pract. 2016;3:460–4.CrossRefGoogle ScholarPubMed
Jiménez-Jiménez, FJ, Alonso-Navarro, H, Martínez, C, et al. The solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, rs3794087 variant and assessment risk for restless legs syndrome. Sleep Med. 2014;15:266–8.CrossRefGoogle ScholarPubMed
Roco, A, Jiménez-Jiménez, FJ, Alonso-Navarro, H, et al. MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome. J Neural Transm (Vienna). 2013;120:463–7.CrossRefGoogle ScholarPubMed
Jiménez-Jiménez, FJ, Alonso-Navarro, H, Martínez, C, et al. Dopamine receptor D3 (DRD3) gene rs6280 variant and risk for restless legs syndrome. Sleep Med. 2013;14:382–4.CrossRefGoogle ScholarPubMed
Jiménez-Jiménez, FJ, Gómez-Tabales, J, Alonso-Navarro, H, et al. LAG3/CD4 genes variants and the risk for restless legs syndrome. Int J Mol Sci. 2022;23:14795.CrossRefGoogle ScholarPubMed
Cho, CH, Choi, JH, Kang, SG, et al. A genome-wide association study identifies UTRN gene polymorphism for restless legs syndrome in a Korean population. Psychiatry Investig. 2017;14:830–8.CrossRefGoogle Scholar
Schormair, B, Zhao, C, Bell, S, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of european ancestry: a meta-analysis. Lancet Neurol. 2017;16:898–907.CrossRefGoogle ScholarPubMed
Didriksen, M, Nawaz, MS, Dowsett, J, et al. Large genome-wide association study identifies three novel risk variants for restless legs syndrome. Commun Biol. 2020;3:703.CrossRefGoogle ScholarPubMed
Lanza, G, Ferri, R. The neurophysiology of hyperarousal in restless legs syndrome: hints for a role of glutamate/GABA. Adv Pharmacol. 2019;84:101–19.CrossRefGoogle ScholarPubMed
Winkelman, JW, Schoerning, L, Platt, S, Jensen, JE. Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity. Sleep Med. 2014;15:1225–30.CrossRefGoogle ScholarPubMed
Burke, RA, Faulkner, MA. Review of the treatment of restless legs syndrome: focus on gabapentin enacarbil. J Cent Nerv Syst Dis. 2012;4:147–56.CrossRefGoogle ScholarPubMed
Mackie, SE, McHugh, RK, McDermott, K, Griffin, ML, Winkelman, JW, Weiss, RD. Prevalence of restless legs syndrome during detoxification from alcohol and opioids. J Subst Abuse Treat. 2017;73:35–9.CrossRefGoogle ScholarPubMed
Batool-Anwar, S, Li, Y, De Vito, K, Malhotra, A, Winkelman, J, Gao, X. Lifestyle factors and risk of restless legs syndrome: prospective Cohort study. J Clin Sleep Med. 2016;12:187–94.CrossRefGoogle ScholarPubMed
Karroum, EG, Saini, PS, Trotti, LM, Rye, DB. TOX3 gene variant could be associated with painful restless legs. Sleep Med. 2020;65:4–7.CrossRefGoogle ScholarPubMed
Peeraully, T, Tan, EK. Genetic variants in sporadic Parkinson’s disease: east vs west. Parkinsonism Relat Disord. 2012;18:S63–5.CrossRefGoogle ScholarPubMed
Peeraully, T, Tan, EK. Linking restless legs syndrome with Parkinson’s disease: clinical, imaging and genetic evidence. Transl Neurodegener. 2012;1:6.CrossRefGoogle ScholarPubMed
Franken, P. A role for clock genes in sleep homeostasis. Curr Opin Neurobiol. 2013;23:864–72.CrossRefGoogle ScholarPubMed
Guo, S, Huang, J, Jiang, H, et al. Restless legs syndrome: from pathophysiology to clinical diagnosis and management. Front Aging Neurosci. 2017;9:171.CrossRefGoogle ScholarPubMed
Poon, HF, Calabrese, V, Scapagnini, G, Butterfield, DA. Free radicals: key to brain aging and heme oxygenase as a cellular response to oxidative stress. J Gerontol A Biol Sci Med Sci. 2004;59:M478–M493.CrossRefGoogle ScholarPubMed
Zhu, XY, Wu, TT, Wang, HM, et al. Correlates of nonanemic iron deficiency in restless legs syndrome. Front Neurol. 2020;11:298.CrossRefGoogle ScholarPubMed
Salminen, AV, Rimpilä, V, Polo, O. Peripheral hypoxia in restless legs syndrome (Willis-Ekbom disease). Neurology. 2014;82:1856–61.CrossRefGoogle ScholarPubMed
Tan, EK, Matsuura, T, Nagamitsu, S, Khajavi, M, Jankovic, J, Ashizawa, T. Polymorphism of NACP-Rep1 in Parkinson’s disease: an etiologic link with essential tremor? Neurology. 2000;54:1195–8.CrossRefGoogle ScholarPubMed
Lahut, S, Vadasz, D, Depboylu, C, et al. The PD-associated alpha-synuclein promoter Rep1 allele 2 shows diminished frequency in restless legs syndrome. Neurogenetics. 2014;15:189–92.CrossRefGoogle ScholarPubMed
Yang, Q, Li, L, Chen, Q, Foldvary-Schaefer, N, Ondo, WG, Wang, QK. Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Med. 2011;12:800–4.CrossRefGoogle Scholar
Schormair, B, Zhao, C, Salminen, AV, Oexle, K, Winkelmann, J, International EU-RLS-GENE Consortium. Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large genome-wide association study dataset of european ancestry. Sleep. 2022;45:zsac098.CrossRefGoogle Scholar
Akçimen, F, Sarayloo, F, Liao, C, et al. Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes. Commun Biol. 2020;3:373.CrossRefGoogle ScholarPubMed
Tam, V, Patel, N, Turcotte, M, Bossé, Y, Paré, G, Meyre, D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20:467–84.CrossRefGoogle ScholarPubMed
Foo, JN, Liu, JJ, Tan, EK. Whole-genome and whole-exome sequencing in neurological diseases. Nat Rev Neurol. 2012;8:508–17.CrossRefGoogle ScholarPubMed
Pavlova, MK, Latreille, V. Sleep disorders. Am J Med. 2019;132:292–9.CrossRefGoogle Scholar