Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis
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 id...
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| Published in: | Lancet neurology Vol. 16; no. 11; pp. 898 - 907 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
England
Elsevier Ltd
01-11-2017
Elsevier Limited Elsevier Lancet Pub. Group |
| Series: | Equipe I |
| Subjects: | |
| Online Access: | Get full text |
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| Abstract | 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.
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.
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).
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.
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. |
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| AbstractList | 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. 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. 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 ) 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. 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). 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. 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. 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. 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. 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. 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). 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. 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. |
| Author | Dauvilliers, Yves Shringarpure, Suyash Rakotozafy, F Balkau, B Shelton, Janie F Bachmann, Cornelius G Tittmann, Lukas Pütz, Benno Pitts, Steven J Bell, Steven Franke, Andre Peters, Annette Allen, Richard P Northover, Carrie AM Xiong, Lan Sathirapongsasuti, J Fah Oertel, Wolfgang H Marre, M Soranzo, Nicole Ondo, William G Elson, Sarah L Hinds, David A Auton, Adam Bell, Robert K Cailleau, M Ross, Owen A Shah, Svati H Danesh, John Bryc, Katarzyna Salminen, Aaro V Perola, Markus Müller-Myhsok, Bertram Gieger, Christian Stefani, Ambra Oexle, Konrad Fietze, Ingo Kleinman, Aaron Rancière, F Di Angelantonio, Emanuele Alhenc-Gelas, F Moreau, JG Rouleau, Guy A Born, C Hadjigeorgiou, Georgios M Polo, Olli Fumeron, F Teder-Laving, Maris Caces, E Earley, Christopher J Litterman, Nadia K Tian, Chao Berger, Klaus Hromatka, Bethann S Winkelmann, Juliane Gan-Or, Ziv Kemlink, David Sonka, Karel Tilch, Erik Girault, A Ducimetière, P Wilson, Catherine H Vacic, Vladimir Bonnefond, A Högl, Birgit Poewe, Werner Gallois, Y Tung, Joyce Y Dina, Christian Eschwège, E Roussel, R Co |
| AuthorAffiliation | ar Inserm UMR1087, CNRS UMR 6291, Institut du Thorax, Nantes, France ae Department of Haematology and BRC Haematology Theme, Churchill Hospital, Oxford, UK az German Centre for Cardiovascular Disease Research (DZHK), Berlin, Germany p Clinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany ah Laboratoire de Neurogénétique, Centre de Recherche, Institut Universitaire en Santé Mentale de Montréal, Montréal, QC, Canada a Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany i National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK s Department of Neurology, University of Ulm, Ulm, Germany an Department of Health, National Institute for Health and Welfare, Helsinki, Finland v Laboratory of Neurogenetics, Department of Neurology, Faculty of Medicine, University of Thessaly, University Hospital of Larissa, Biopolis, Larissa, Greece ac Department of |
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y Department of Cardiology and Angiology, Centre of Sleep Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany – name: ac Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK – name: bf 23andMe, Mountain View, CA, USA – name: be Neurologische Klinik und Poliklinik, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany – name: e MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK – name: j Max Planck Institute of Psychiatry, Munich, Germany – name: ba Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany – name: t Neuropsychiatry Centre Erding/München, Erding, Germany – name: k Sleep-Wake Disorders Centre, Department of Neurology, Hôpital Gui-de-Chauliac, INSERM U1061, CHU Montpellier, France – name: ae Department of Haematology and BRC Haematology Theme, Churchill Hospital, Oxford, UK – name: au PopGen Biobank and Institute of Epidemiology, Christian Albrechts University Kiel, Kiel, Germany – name: aq Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic – name: q Paracelsus-Elena Hospital, Centre of Parkinsonism and Movement Disorders, Kassel, Germany – name: ay German Centre for Diabetes Research (DZD), Neuherberg, Germany – name: w Unesta Research Centre, Tampere, Finland – name: al Hôpital du Sacré-Coeur de Montréal, 67120, Center for Advanced Research in Sleep Medicine, Montréal, QC, Canada – name: ab British Heart Foundation Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, UK – name: bc Institute of Translational Medicine, University of Liverpool, Liverpool, UK – name: o Department of Clinical Neurophysiology, University Medical Centre, Georg August University Göttingen, Göttingen, Germany – name: bb Munich Cluster for Systems Neurology (SyNergy), Munich, Germany – name: ad Radcliffe Department of Medicine, BRC Haematology Theme and NHS Blood and Transplant, John Radcliffe Hospital, Headington, Oxford, UK – name: d National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics at the University of Cambridge, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK – name: s Department of Neurology, University of Ulm, Ulm, Germany – name: ag Department of Neurology, Methodist Neurological Institute, Houston, TX, USA – name: af Center for Restless Legs Study, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA – name: ar Inserm UMR1087, CNRS UMR 6291, Institut du Thorax, Nantes, France – name: ax Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA – name: f Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK – name: ao Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic – name: c Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany – name: n Department of Neurology, Paracelsus Klinik, Osnabrueck, Germany – name: aw Department of Medicine, Duke University School of Medicine, Durham, NC, USA – name: p Clinic for Neurosurgery, University Medical Centre, Georg August University Göttingen, Göttingen, Germany – name: m Department of Neurology and Centre of Clinical Neuroscience, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic – name: bd Institute of Human Genetics, Technische Universität München, Munich, Germany – name: av John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada – name: a Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany – name: h NHS Blood and Transplant, Cambridge, UK – name: z Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA – name: as Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, France – name: b Institute of Epidemiology II, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany – name: i National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, UK – name: aj Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada – name: x Department of Pulmonary Diseases, Tampere University Hospital, Tampere, Finland – name: l Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria – name: an Department of Health, National Institute for Health and Welfare, Helsinki, Finland – name: ah Laboratoire de Neurogénétique, Centre de Recherche, Institut Universitaire en Santé Mentale de Montréal, Montréal, QC, Canada |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29029846$$D View this record in MEDLINE/PubMed https://hal.science/hal-01832985$$DView record in HAL |
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| Copyright | 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. Copyright Elsevier Limited Nov 1, 2017 Distributed under a Creative Commons Attribution 4.0 International License 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license 2017 |
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| Keywords | Genome-Wide Association Study Genetic Predisposition to Disease Semaphorins Humans GPI-Linked Proteins Restless Legs Syndrome European Continental Ancestry Group Transcription Factors Nerve Tissue Proteins DNA-Binding Proteins |
| Language | English |
| License | This is an open access article under the CC BY license. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. Distributed under a Creative Commons Attribution 4.0 International License: http://creativecommons.org/licenses/by/4.0 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
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| Snippet | Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of... Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS... BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer... |
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| SubjectTerms | Amyotrophic lateral sclerosis Brain research Datasets DNA-Binding Proteins - genetics Genes Genetic Predisposition to Disease - genetics Genome-Wide Association Study Genomes GPI-Linked Proteins - genetics Humans Insomnia Life Sciences Medical research Meta-analysis Nerve Tissue Proteins - genetics Netrins Neurogenesis Neurological diseases Pathogenesis Population Restless legs syndrome Restless Legs Syndrome - epidemiology Restless Legs Syndrome - genetics Semaphorins - genetics Sleep deprivation Studies Systematic review Transcription Factors - genetics White People |
| Title | Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis |
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