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

Juliane Winkelmann; Darina Czamara; Barbara Schormair; Franziska Knauf; Eva Schulte; Claudia Trenkwalder; Yves Dauvilliers; Olli Polo; Birgit Högl; Klaus Berger; Andrea Fuhs; Nadine Gross; Karin Stiasny-Kolster; Wolfgang Oertel; Cornelius Bachmann; Walter Paulus; Lan Xiong; Jacques Montplaisir; Guy Rouleau; Ingo Fietze; Jana Vávrová; David Kemlink; Karel Sonka; Sona Nevsimalova; Siong-Chi Lin; Zbigniew Wszolek; Carles Vilariño-Güell; Matthew Farrer; Viola Gschliesser; Birgit Frauscher; Tina Falkenstetter; Werner Poewe; Richard Allen; Christopher Earley; William Ondo; Wei-Dong Le; Derek Spieler; Maria Kaffe; Alexander Zimprich; Johannes Kettunen; Markus Perola; Kaisa Silander; Isabelle Cournu-Rebeix; Marcella Francavilla; Claire Fontenille; Bertrand Fontaine; Pavel Vodicka; Holger Prokisch; Peter Lichtner; Paul Peppard; Juliette Faraco; Emmanuel Mignot; Christian Gieger; Thomas Illig; H-Erich Wichmann; Bertram Müller-Myhsok; Thomas Meitinger

doi:10.1371/journal.pgen.1002171

Journal articles

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

Juliane Winkelmann ^{1, 2, 3, *} Darina Czamara ⁴ Barbara Schormair ^{1, 3} Franziska Knauf ^{1, 3} Eva Schulte ² Claudia Trenkwalder ⁵ Yves Dauvilliers ⁶ Olli Polo ^{7, 8} Birgit Högl ⁹ Klaus Berger ¹⁰ Andrea Fuhs ¹⁰ Nadine Gross ² Karin Stiasny-Kolster ^{11, 12} Wolfgang Oertel ¹² Cornelius Bachmann ¹³ Walter Paulus ¹³ Lan Xiong ¹⁴ Jacques Montplaisir ^{15, 16} Guy Rouleau ¹⁴ Ingo Fietze ¹⁷ Jana Vávrová ¹⁸ David Kemlink ¹⁸ Karel Sonka ¹⁸ Sona Nevsimalova ¹⁸ Siong-Chi Lin ¹⁹ Zbigniew Wszolek ¹⁹ Carles Vilariño-Güell ¹⁹ Matthew Farrer ¹⁹ Viola Gschliesser ⁹ Birgit Frauscher ⁹ Tina Falkenstetter ⁹ Werner Poewe ⁹ Richard Allen ²⁰ Christopher Earley ²⁰ William Ondo ²¹ Wei-Dong Le ²¹ Derek Spieler ^{1, 3} Maria Kaffe ^{2, 3} Alexander Zimprich ²² Johannes Kettunen ^{23, 24} Markus Perola ^{23, 24} Kaisa Silander ^{23, 24} Isabelle Cournu-Rebeix ²⁵ Marcella Francavilla ²⁵ Claire Fontenille ²⁵ Bertrand Fontaine ²⁵ Pavel Vodicka ²⁶ Holger Prokisch ^{3, 1} Peter Lichtner ^{1, 3} Paul Peppard ²⁷ Juliette Faraco ²⁸ Emmanuel Mignot ²⁸ Christian Gieger ²⁹ Thomas Illig ³⁰ H-Erich Wichmann ^{31, 32, 33} Bertram Müller-Myhsok ⁴ Thomas Meitinger ^{1, 3}

* Corresponding author

1 Institute of Human Genetics

2 Department of Neurology

3 Institute of Human Genetics

4 Max-Planck-Institut für Psychiatrie

5 Center of Parkinsonism and Movement Disorders

6 Neuropsychiatrie : recherche épidémiologique et clinique

7 Sleep Research Unit

8 Department of Pulmonary Medicine

9 Department of Neurology

10 Institute of Epidemiology and Social Medicine

11 Somnomar

12 Department of Neurology

13 Department of Clinical Neurophysiology

14 Center of Excellence in Neuroscience

15 Laboratoire d'étude des maladies du cerveau

16 Centre d'étude du sommeil

17 Interdisciplinary Center of Sleep Medicine

18 Department of Neurology

19 Centre for Molecular Medicine and Therapeutics

20 Department of Neurology

21 Department of Neurology

22 Department of Neurology

23 FIMM - Institute for Molecular Medicine Finland [Helsinki]

24 Department of Chronic Disease Prevention

25 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière

26 Institute of Experimental Medicine

27 Department of Population Health Sciences

28 Center For Narcolepsy

29 Institute of Genetic Epidemiology

30 Unit for Molecular Epidemiology

31 Institute of Medical Informatics, Biometry, and Epidemiology

32 Institute of Epidemiology I

33 Klinikum Großhadern

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

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