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Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

Publication ,  Journal Article
Schormair, B; Zhao, C; Bell, S; Tilch, E; Salminen, AV; Pütz, B; Dauvilliers, Y; Stefani, A; Högl, B; Poewe, W; Kemlink, D; Sonka, K; Polo, O ...
Published in: Lancet Neurol
November 2017

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10-8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

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Published In

Lancet Neurol

DOI

EISSN

1474-4465

Publication Date

November 2017

Volume

16

Issue

11

Start / End Page

898 / 907

Location

England

Related Subject Headings

  • White People
  • Transcription Factors
  • Semaphorins
  • Restless Legs Syndrome
  • Neurology & Neurosurgery
  • Netrins
  • Nerve Tissue Proteins
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease
 

Citation

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Schormair, B., Zhao, C., Bell, S., Tilch, E., Salminen, A. V., Pütz, B., … DESIR study group. (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
Schormair, Barbara, Chen Zhao, Steven Bell, Erik Tilch, Aaro V. Salminen, Benno Pütz, Yves Dauvilliers, 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 16, no. 11 (November 2017): 898–907. https://doi.org/10.1016/S1474-4422(17)30327-7.
Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, 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 Nov;16(11):898–907.
Schormair, Barbara, 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, vol. 16, no. 11, Nov. 2017, pp. 898–907. Pubmed, doi:10.1016/S1474-4422(17)30327-7.
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, 23andMe Research Team, DESIR study group. 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 Nov;16(11):898–907.
Journal cover image

Published In

Lancet Neurol

DOI

EISSN

1474-4465

Publication Date

November 2017

Volume

16

Issue

11

Start / End Page

898 / 907

Location

England

Related Subject Headings

  • White People
  • Transcription Factors
  • Semaphorins
  • Restless Legs Syndrome
  • Neurology & Neurosurgery
  • Netrins
  • Nerve Tissue Proteins
  • Humans
  • Genome-Wide Association Study
  • Genetic Predisposition to Disease