Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2 p 14 and 16 q 12 . 1

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 = 9.036 10, OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.46 10, OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 59-end of TOX3 and the adjacent non-coding RNA BC034767. PLoS Genetics | www.plosgenetics.org 1 July 2011 | Volume 7 | Issue 7 | e1002171 Citation: Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, et al. (2011) Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1. PLoS Genet 7(7): e1002171. doi:10.1371/journal.pgen.1002171 Editor: Mark I. McCarthy, University of Oxford, United Kingdom Received December 7, 2010; Accepted May 24, 2011; Published July 14, 2011 Copyright: 2011 Winkelmann et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The replication phase was supported by a grant from the US RLS Foundation. Part of this work was financed by the National Genome Research Network (NGFN). The KORA study group consists of H-E Wichmann (speaker), R Holle, J John, T Illig, C Meisinger, A Peters, and their coworkers, who are responsible for the design and conduction of the KORA studies. The KORA research platform (KORA, Cooperative Research in the Region of Augsburg) was initiated and financed by the Helmholtz Zentrum München, which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. The collection of sociodemographic and clinical data in the Dortmund Health Study was supported by the German Migraine & Headache Society (DMKG) and by unrestricted grants of equal share from Astra Zeneca, Berlin Chemie, Boots Healthcare, Glaxo-Smith-Kline, McNeil Pharma (former Woelm Pharma), MSD Sharp & Dohme, and Pfizer to the University of Muenster. Blood collection in the Dortmund Health Study was done through funds from the Institute of Epidemiology and Social Medicine, University of Muenster. Data collection in the COR-Study was supported by unrestricted grants of the German RLS Society (Deutsche Restless Legs Vereinigung e.V.) and Axxonis Pharma, Boehringer Ingelheim Pharma, Mundipharma Research, Roche Pharma, and UCB to the University of Muenster. CG Bachmann was supported by grants of the German RLS Society, Deutsche Restless Legs Vereinigung, e.V. H Prokisch and T Meitinger were supported by the German Federal Ministry of Education and Research (BMBF) project Systems Biology of Metabotypes (SysMBo#0315494A). RP Allen and CJ Earley were supported by the grant PO1-AG21190 National Institute of Health, USA; the Canadian part of the study was supported by a Canadian Institutes of Health Research (CIHR) grant to GA Rouleau and J Montplaisir. D Kemlink and S Nevsimalova were supported by an ESRS grant MSM0021620849; Jávrová and K Sonka were supported by grant MSM0021620816. Recruitment of Czech controls was funded by grant IGA NR 8563-5, Ministry of Health of the Czech Republic. B Frauscher, I Cournu-Rebeix, M Francavilla, and C Fontenille are co-authors on behalf of BRC-REFGENSEP, which is supported by INSERM, AFM (Généthon), ARSEP, and GIS-IBISA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: winkelmann@lrz.tu-muenchen.de . These authors contributed equally to this work.

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