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Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

ABSTRACT: Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, P?=?9.03 × 10(-11), OR?=?1.23) and a locus on 16q12.1 (rs3104767, P?=?9.4 × 10(-19), OR?=?1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

SUBMITTER: Winkelmann J

PROVIDER: S-EPMC3136436 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

Winkelmann Juliane J Czamara Darina D Schormair Barbara B Knauf Franziska F Schulte Eva C EC Trenkwalder Claudia C Dauvilliers Yves Y Polo Olli O Högl Birgit B Berger Klaus K Fuhs Andrea A Gross Nadine N Stiasny-Kolster Karin K Oertel Wolfgang W Bachmann Cornelius G CG Paulus Walter W Xiong Lan L Montplaisir Jacques J Rouleau Guy A GA Fietze Ingo I Vávrová Jana J Kemlink David D Sonka Karel K Nevsimalova Sona S Lin Siong-Chi SC Wszolek Zbigniew Z Vilariño-Güell Carles C Farrer Matthew J MJ Gschliesser Viola V Frauscher Birgit B Falkenstetter Tina T Poewe Werner W Allen Richard P RP Earley Christopher J CJ Ondo William G WG Le Wei-Dong WD Spieler Derek D Kaffe Maria M Zimprich Alexander A Kettunen Johannes J Perola Markus M Silander Kaisa K Cournu-Rebeix Isabelle I Francavilla Marcella M Fontenille Claire C Fontaine Bertrand B Vodicka Pavel P Prokisch Holger H Lichtner Peter P Peppard Paul P Faraco Juliette J Mignot Emmanuel E Gieger Christian C Illig Thomas T Wichmann H-Erich HE Müller-Myhsok Bertram B Meitinger Thomas T

PLoS genetics 20110714 7

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conduct ...[more]

PMID: 21779176

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Project description:BackgroundRestless 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.MethodsIn 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.FindingsWe 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).InterpretationIdentification 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.FundingDeutsche 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.

Dataset Information

Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

Publications

Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1.

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