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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.

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Figure 1: Study overview.
Figure 2: Extent of population stratification.
Figure 3: Genome-wide association study for RLS susceptibility loci.
Figure 4: Pairwise linkage disequilibrium diagrams for three RLS-associated loci.
Figure 5: Haplotype structure for MEIS1.

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Acknowledgements

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 part of the study was supported by a Canadian Institutes of Health Research (CIHR) grant to G.R, J.M and G.T.

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Contributions

Study design: J.W., P.L., G.R., F.H., B.M.-M., T.M.; recruitment and biobanking of individuals with RLS: J.W., S.H., C.T., A.Z., K.S.-K., W.O., C.B., W.P., I.P., I.E., T.M.; recruitment and biobanking of KORA controls: C.G., T.I., H.-E.W.; recruitment and biobanking of Canadian affected individuals and controls: L.X., J.M., G.T., G.R.; Affymetrix genotyping: B.S., P.L., G.E.; Sequenom genotyping: B.S., P.L., S.J.; supervision of typing of all markers: J.W., P.L.; software development and data processing: S.R.,B.P.; statistical analysis: S.R., B.P., B.M.-M.; clustering of Affymetrix genotypes: S.R., B.M.-M.; manuscript writing: J.W., B.S., S.F., L.X., F.H., B.M.-M., T.M.

Corresponding authors

Correspondence to Juliane Winkelmann or Thomas Meitinger.

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Competing interests

J.W., B.S., P.L., B.M.-M., F.H. and T.M. have filed a patent application.

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Winkelmann, J., Schormair, B., Lichtner, P. et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 39, 1000–1006 (2007). https://doi.org/10.1038/ng2099

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