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 C. Schulte; Claudia Trenkwalder; Yves Dauvilliers; Olli Polo; Birgit Högl; Klaus Berger; Andrea Fuhs; Nadine Gross; Karin Stiasny-Kolster; Wolfgang Oertel; Cornelius G. Bachmann; Walter Paulus; Lan Xiong; Jacques Montplaisir; Guy A. Rouleau; Ingo Fietze; Jana Vávrová; David Kemlink; Karel Sonka; Sona Nevsimalova; Siong Chi Lin; Zbigniew Wszolek; Carles Vilariño-Güell; Matthew J. Farrer; Viola Gschliesser; Birgit Frauscher; Tina Falkenstetter; Werner Poewe; Richard P. Allen; Christopher J. Earley; William G. 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

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 C. Schulte, Claudia Trenkwalder, Yves Dauvilliers, Olli Polo, Birgit Högl, Klaus Berger, Andrea Fuhs, Nadine Gross, Karin Stiasny-Kolster, Wolfgang Oertel, Cornelius G. Bachmann, Walter Paulus, Lan Xiong, Jacques Montplaisir, Guy A. Rouleau, Ingo FietzeJana Vávrová, David Kemlink, Karel Sonka, Sona Nevsimalova, Siong Chi Lin, Zbigniew Wszolek, Carles Vilariño-Güell, Matthew J. Farrer, Viola Gschliesser, Birgit Frauscher, Tina Falkenstetter, Werner Poewe, Richard P. Allen, Christopher J. Earley, William G. 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

Neurology

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134 Scopus citations

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.

Original language	English (US)
Article number	e1002171
Journal	PLoS genetics
Volume	7
Issue number	7
DOIs	https://doi.org/10.1371/journal.pgen.1002171
State	Published - Jul 2011

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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Winkelmann, J., Czamara, D., Schormair, B., Knauf, F., Schulte, E. C., Trenkwalder, C., Dauvilliers, Y., Polo, O., Högl, B., Berger, K., Fuhs, A., Gross, N., Stiasny-Kolster, K., Oertel, W., Bachmann, C. G., Paulus, W., Xiong, L., Montplaisir, J., Rouleau, G. A., ... Meitinger, T. (2011). Genome-Wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS genetics, 7(7), Article e1002171. https://doi.org/10.1371/journal.pgen.1002171

Winkelmann, J, Czamara, D, Schormair, B, Knauf, F, Schulte, EC, Trenkwalder, C, Dauvilliers, Y, Polo, O, Högl, B, Berger, K, Fuhs, A, Gross, N, Stiasny-Kolster, K, Oertel, W, Bachmann, CG, Paulus, W, Xiong, L, Montplaisir, J, Rouleau, GA, Fietze, I, Vávrová, J, Kemlink, D, Sonka, K, Nevsimalova, S, Lin, SC, Wszolek, Z, Vilariño-Güell, C, Farrer, MJ, Gschliesser, V, Frauscher, B, Falkenstetter, T, Poewe, W, Allen, RP, Earley, CJ, Ondo, WG, Le, WD, Spieler, D, Kaffe, M, Zimprich, A, Kettunen, J, Perola, M, Silander, K, Cournu-Rebeix, I, Francavilla, M, Fontenille, C, Fontaine, B, Vodicka, P, Prokisch, H, Lichtner, P, Peppard, P, Faraco, J, Mignot, E, Gieger, C, Illig, T, Wichmann, HE, Müller-Myhsok, B & Meitinger, T 2011, 'Genome-Wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1', PLoS genetics, vol. 7, no. 7, e1002171. https://doi.org/10.1371/journal.pgen.1002171

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title = "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.",

author = "Juliane Winkelmann and Darina Czamara and Barbara Schormair and Franziska Knauf and Schulte, {Eva C.} and Claudia Trenkwalder and Yves Dauvilliers and Olli Polo and Birgit H{\"o}gl and Klaus Berger and Andrea Fuhs and Nadine Gross and Karin Stiasny-Kolster and Wolfgang Oertel and Bachmann, {Cornelius G.} and Walter Paulus and Lan Xiong and Jacques Montplaisir and Rouleau, {Guy A.} and Ingo Fietze and Jana V{\'a}vrov{\'a} and David Kemlink and Karel Sonka and Sona Nevsimalova and Lin, {Siong Chi} and Zbigniew Wszolek and Carles Vilari{\~n}o-G{\"u}ell and Farrer, {Matthew J.} and Viola Gschliesser and Birgit Frauscher and Tina Falkenstetter and Werner Poewe and Allen, {Richard P.} and Earley, {Christopher J.} and Ondo, {William G.} and Le, {Wei Dong} and Derek Spieler and Maria Kaffe and Alexander Zimprich and Johannes Kettunen and Markus Perola and Kaisa Silander and Isabelle Cournu-Rebeix and Marcella Francavilla and Claire Fontenille and Bertrand Fontaine and Pavel Vodicka and Holger Prokisch and Peter Lichtner and Paul Peppard and Juliette Faraco and Emmanuel Mignot and Christian Gieger and Thomas Illig and Wichmann, {H. Erich} and Bertram M{\"u}ller-Myhsok and Thomas Meitinger",

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AU - Winkelmann, Juliane

AU - Czamara, Darina

AU - Schormair, Barbara

AU - Knauf, Franziska

AU - Schulte, Eva C.

AU - Trenkwalder, Claudia

AU - Dauvilliers, Yves

AU - Polo, Olli

AU - Högl, Birgit

AU - Berger, Klaus

AU - Fuhs, Andrea

AU - Gross, Nadine

AU - Stiasny-Kolster, Karin

AU - Oertel, Wolfgang

AU - Bachmann, Cornelius G.

AU - Paulus, Walter

AU - Xiong, Lan

AU - Montplaisir, Jacques

AU - Rouleau, Guy A.

AU - Fietze, Ingo

AU - Vávrová, Jana

AU - Kemlink, David

AU - Sonka, Karel

AU - Nevsimalova, Sona

AU - Lin, Siong Chi

AU - Wszolek, Zbigniew

AU - Vilariño-Güell, Carles

AU - Farrer, Matthew J.

AU - Gschliesser, Viola

AU - Frauscher, Birgit

AU - Falkenstetter, Tina

AU - Poewe, Werner

AU - Allen, Richard P.

AU - Earley, Christopher J.

AU - Ondo, William G.

AU - Le, Wei Dong

AU - Spieler, Derek

AU - Kaffe, Maria

AU - Zimprich, Alexander

AU - Kettunen, Johannes

AU - Perola, Markus

AU - Silander, Kaisa

AU - Cournu-Rebeix, Isabelle

AU - Francavilla, Marcella

AU - Fontenille, Claire

AU - Fontaine, Bertrand

AU - Vodicka, Pavel

AU - Prokisch, Holger

AU - Lichtner, Peter

AU - Peppard, Paul

AU - Faraco, Juliette

AU - Mignot, Emmanuel

AU - Gieger, Christian

AU - Illig, Thomas

AU - Wichmann, H. Erich

AU - Müller-Myhsok, Bertram

AU - Meitinger, Thomas

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N2 - 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.

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

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