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

Autor: Schormair, Barbara, Zhao, Chen, Bell, Steven, Tilch, Erik, Salminen, Aaro V., Pütz, Benno, Dauvilliers, Yves, Stefani, Ambra, Högl, Birgit, Poewe, Werner, Kemlink, David, Sonka, Karel, Bachmann, Cornelius G., Paulus, Walter, Trenkwalder, Claudia, Oertel, Wolfgang H., Hornyak, Magdolna, Teder-Laving, Maris, Metspalu, Andres, Hadjigeorgiou, Georgios M., Polo, Olli, Fietze, Ingo, Ross, Owen A., Wszolek, Zbigniew, Butterworth, Adam S., Soranzo, Nicole, Ouwehand, Willem H., Roberts, David J., Danesh, John, Allen, Richard P., Earley, Christopher J., Ondo, William G., Xiong, Lan, Montplaisir, Jacques, Gan-Or, Ziv, Perola, Markus, Vodicka, Pavel, Dina, Christian, Franke, Andre, Tittmann, Lukas, Stewart, Alexandre F. R., Shah, Svati H., Gieger, Christian, Peters, Annette, Rouleau, Guy A., Berger, Klaus, Oexle, Konrad, Di Angelantonio, Emanuele, Hinds, David A., Müller-Myhsok, Bertram, Winkelmann, Juliane, Team, 23andMe Research, group, DESIR
Přispěvatelé: Institute of Human Genetics, Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Statistical Genetics Group, Metacohorts Consortium, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Department of Neurology, Innsbruck Medical University [Austria] (IMU), Charles University [Prague]-1st Faculty of Medicine, First Faculty of Medicine and General Teaching Hospital [Prague, Czech Republic], Charles university in Prague (CZECH REPUBLIC), Department of Clinical Neurophysiology [Göttingen], Georg-August-University [Göttingen], Paracelsus Elena Klinik, Centre for Parkinson's Disease & Movement Disorders, University of Tartu, Sleep Research Unit, University of Turku, Department of Pulmonary Medicine, Tampere University Hospital, Interdisciplinary Center of Sleep Medicine, Universitätsmedizin Berlin-Internetseiten der Charité, Centre for Molecular Medicine and Therapeutics, University of British Columbia (UBC), Department of Public Health & Primary Care, University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], Center of Excellence in Neuroscience, CHU de Montréal, Hôpital du Sacré-Coeur de Montréal, Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (ASCR), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Center For Narcolepsy, Stanford University [Stanford], Center of Excellence in Neuromics, University of Montreal, Institute of Human Genetics, Technische Universität München, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Bell, Steven [0000-0001-6774-3149], Butterworth, Adam [0000-0002-6915-9015], Soranzo, Nicole [0000-0003-1095-3852], Ouwehand, Willem [0000-0002-7744-1790], Danesh, John [0000-0003-1158-6791], Di Angelantonio, Emanuele [0000-0001-8776-6719], Apollo - University of Cambridge Repository, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Charles University [Prague] (CU)-1st Faculty of Medicine, Charles University [Prague] (CU), Czech Academy of Sciences [Prague] (CAS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Stanford University, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2017
Předmět:
Zdroj: The Lancet Neurology
The Lancet Neurology, Elsevier, 2017, Equipe I, 16 (11), pp.898--907. ⟨10.1016/S1474-4422(17)30327-7⟩
ISSN: 1474-4422
1474-4465
DOI: 10.1016/S1474-4422(17)30327-7⟩
Popis: International audience; 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: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) 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.
Databáze: OpenAIRE
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