Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Authors: Barbara Schormair, Chen Zhao, Steven Bell, Erik Tilch, Aaro V. Salminen, Benno Pütz, Yves Dauvilliers, Ambra Stefani, Birgit Högl, Werner Poewe, David Kemlink, Karel Šonka, Cornelius G. Bachmann, Walter Paulus, Claudia Trenkwalder, Wolfgang H. Oertel, Magdolna Hornyak, Maris Teder‐Laving, Andres Metspalu, Georgios M. Hadjigeorgiou, Olli Polo, Ingo Fietze, Owen A. Ross, Zbigniew K. Wszołek, Adam S. Butterworth, Nicole Soranzo, Willem H. Ouwehand, David J. Roberts, John Danesh, Richard P. Allen, Christopher J. Earley, William G. Ondo, Lan Xiong, Jacques Montplaisir, Ziv Gan‐Or, Markus Perola, Pavel Vodička, Christian Dina, André Franke, Lukas Tittmann, Alexandre F.R. Stewart, Svati H. Shah, Christian Gieger, Annette Peters, Guy A. Rouleau, Klaus Berger, Konrad Oexle, Emanuele Di Angelantonio, David A. Hinds, Bertram Müller‐Myhsok, Juliane Winkelmann, Beverley Balkau, Pierre Ducimetière, Eveline Eschwège, Fanny Rancière, François Alhenc‐Gelas, Yves Gallois, A Girault, Frédéric Fumeron, Michel Marre, Ronan Roussel, Fabrice Bonnet, Amélie Bonnefond, Stéphane Cauchi, Philippe Froguel, Joël Cogneau, C. Born, E Cacès, M. Cailleau, Olivier Lantieri, J.G. Moreau, F Rakotozafy, Jean Tichet, Sylviane Vol, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Bethann S. Hromatka, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Matthew H. McIntyre, Joanna L. Mountain, Carrie A. M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, Catherine H. Wilson - The Lancet 2017 cited by 240

BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. METHODS: ) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.