Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

Juliane Winkelmann; Barbara Schormair; Peter Lichtner; Stephan Ripke; Lan Xiong; Shapour Jalilzadeh; Stephany Fulda; Benno Pütz; Gertrud Eckstein; Stephanie Hauk; Claudia Trenkwalder; Alexander Zimprich; Karin Stiasny-Kolster; Wolfgang Oertel; Cornelius G. Bachmann; Walter Paulus; Ines Peglau; Ilonka Eisensehr; Jacques Montplaisir; Gustavo Turecki; Guy Rouleau; Christian Gieger; Thomas Illig; H. Erich Wichmann; Florian Holsboer; Bertram Müller-Myhsok; Thomas Meitinger

doi:10.1038/ng2099

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

Juliane Winkelmann, Barbara Schormair, Peter Lichtner, Stephan Ripke, Lan Xiong, Shapour Jalilzadeh, Stephany Fulda, Benno Pütz, Gertrud Eckstein, Stephanie Hauk, Claudia Trenkwalder, Alexander Zimprich, Karin Stiasny-Kolster, Wolfgang Oertel, Cornelius G. Bachmann, Walter Paulus, Ines Peglau, Ilonka Eisensehr, Jacques Montplaisir, Gustavo TureckiGuy Rouleau, Christian Gieger, Thomas Illig, H. Erich Wichmann, Florian Holsboer, Bertram Müller-Myhsok, Thomas Meitinger

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Abstract

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

Original language	English
Pages (from-to)	1000-1006
Number of pages	7
Journal	Nature Genetics
Volume	39
Issue number	8
DOIs	https://doi.org/10.1038/ng2099
State	Published - Aug 2007

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Winkelmann, J., Schormair, B., Lichtner, P., Ripke, S., Xiong, L., Jalilzadeh, S., Fulda, S., Pütz, B., Eckstein, G., Hauk, S., Trenkwalder, C., Zimprich, A., Stiasny-Kolster, K., Oertel, W., Bachmann, C. G., Paulus, W., Peglau, I., Eisensehr, I., Montplaisir, J., ... Meitinger, T. (2007). Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nature Genetics, 39(8), 1000-1006. https://doi.org/10.1038/ng2099

@article{089c85440de94bd992c84de85b5b0a33,

title = "Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions",

abstract = "Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.",

author = "Juliane Winkelmann and Barbara Schormair and Peter Lichtner and Stephan Ripke and Lan Xiong and Shapour Jalilzadeh and Stephany Fulda and Benno P{\"u}tz and Gertrud Eckstein and Stephanie Hauk and Claudia Trenkwalder and Alexander Zimprich and Karin Stiasny-Kolster and Wolfgang Oertel and Bachmann, {Cornelius G.} and Walter Paulus and Ines Peglau and Ilonka Eisensehr and Jacques Montplaisir and Gustavo Turecki and Guy Rouleau and Christian Gieger and Thomas Illig and Wichmann, {H. Erich} and Florian Holsboer and Bertram M{\"u}ller-Myhsok and Thomas Meitinger",

note = "Funding Information: We are grateful to all patients who participated in this study. The authors also thank T.M. Strom, J. Favor, D. Vogt-Weisenhorn, W. Wurst and I. Tews for discussions and R. Feldmann, J. Golic, K. Junghans, B. Schmick, N. Trapp, M. Petzold, G. Fischer and M. Putz for technical assistance. We acknowledge L. Habersack, H. Rhese and J. Schmidt-Evers from the German RLS patient organization for supporting this study. 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 co-workers, who are responsible for the design and conduct of the KORA studies. The KORA (Cooperative Research in the Region of Augsburg) research project was initiated and financed by the National Research Centre for Environment and Health (GSF), which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. S.H. was partly supported by a grant from the German RLS patient organization. J.W. was partly supported by a grant form the Bavarian Ministry of Science, Culture and Art. The Canadian Funding Information: part of the study was supported by a Canadian Institutes of Health Research (CIHR) grant to G.R, J.M and G.T.",

year = "2007",

month = aug,

doi = "10.1038/ng2099",

language = "English",

volume = "39",

pages = "1000--1006",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

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Winkelmann, J, Schormair, B, Lichtner, P, Ripke, S, Xiong, L, Jalilzadeh, S, Fulda, S, Pütz, B, Eckstein, G, Hauk, S, Trenkwalder, C, Zimprich, A, Stiasny-Kolster, K, Oertel, W, Bachmann, CG, Paulus, W, Peglau, I, Eisensehr, I, Montplaisir, J, Turecki, G, Rouleau, G, Gieger, C, Illig, T, Wichmann, HE, Holsboer, F, Müller-Myhsok, B & Meitinger, T 2007, 'Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions', Nature Genetics, vol. 39, no. 8, pp. 1000-1006. https://doi.org/10.1038/ng2099

TY - JOUR

T1 - Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

AU - Winkelmann, Juliane

AU - Schormair, Barbara

AU - Lichtner, Peter

AU - Ripke, Stephan

AU - Xiong, Lan

AU - Jalilzadeh, Shapour

AU - Fulda, Stephany

AU - Pütz, Benno

AU - Eckstein, Gertrud

AU - Hauk, Stephanie

AU - Trenkwalder, Claudia

AU - Zimprich, Alexander

AU - Stiasny-Kolster, Karin

AU - Oertel, Wolfgang

AU - Bachmann, Cornelius G.

AU - Paulus, Walter

AU - Peglau, Ines

AU - Eisensehr, Ilonka

AU - Montplaisir, Jacques

AU - Turecki, Gustavo

AU - Rouleau, Guy

AU - Gieger, Christian

AU - Illig, Thomas

AU - Wichmann, H. Erich

AU - Holsboer, Florian

AU - Müller-Myhsok, Bertram

AU - Meitinger, Thomas

N1 - Funding Information: We are grateful to all patients who participated in this study. The authors also thank T.M. Strom, J. Favor, D. Vogt-Weisenhorn, W. Wurst and I. Tews for discussions and R. Feldmann, J. Golic, K. Junghans, B. Schmick, N. Trapp, M. Petzold, G. Fischer and M. Putz for technical assistance. We acknowledge L. Habersack, H. Rhese and J. Schmidt-Evers from the German RLS patient organization for supporting this study. 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 co-workers, who are responsible for the design and conduct of the KORA studies. The KORA (Cooperative Research in the Region of Augsburg) research project was initiated and financed by the National Research Centre for Environment and Health (GSF), which is funded by the German Federal Ministry of Education and Research and by the State of Bavaria. S.H. was partly supported by a grant from the German RLS patient organization. J.W. was partly supported by a grant form the Bavarian Ministry of Science, Culture and Art. The Canadian Funding Information: part of the study was supported by a Canadian Institutes of Health Research (CIHR) grant to G.R, J.M and G.T.

PY - 2007/8

Y1 - 2007/8

N2 - Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

AB - Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

UR - http://www.scopus.com/inward/record.url?scp=34547497308&partnerID=8YFLogxK

U2 - 10.1038/ng2099

DO - 10.1038/ng2099

M3 - Article

C2 - 17637780

AN - SCOPUS:34547497308

SN - 1061-4036

VL - 39

SP - 1000

EP - 1006

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

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