TY - JOUR
T1 - Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry
T2 - a meta-analysis
AU - 23andMe Research Team
AU - DESIR study group
AU - 23andMe Research Team
AU - DESIR study group
AU - DESIR study group
AU - DESIR study group
AU - Schormair, Barbara
AU - Zhao, Chen
AU - Bell, Steven
AU - Tilch, Erik
AU - Salminen, Aaro V.
AU - Pütz, Benno
AU - Dauvilliers, Yves
AU - Stefani, Ambra
AU - Högl, Birgit
AU - Poewe, Werner
AU - Kemlink, David
AU - Sonka, Karel
AU - Bachmann, Cornelius G.
AU - Paulus, Walter
AU - Trenkwalder, Claudia
AU - Oertel, Wolfgang H.
AU - Hornyak, Magdolna
AU - Teder-Laving, Maris
AU - Metspalu, Andres
AU - Hadjigeorgiou, Georgios M.
AU - Polo, Olli
AU - Fietze, Ingo
AU - Ross, Owen A.
AU - Wszolek, Zbigniew
AU - Butterworth, Adam S.
AU - Soranzo, Nicole
AU - Ouwehand, Willem H.
AU - Roberts, David J.
AU - Danesh, John
AU - Allen, Richard P.
AU - Earley, Christopher J.
AU - Ondo, William G.
AU - Xiong, Lan
AU - Montplaisir, Jacques
AU - Gan-Or, Ziv
AU - Perola, Markus
AU - Vodicka, Pavel
AU - Dina, Christian
AU - Franke, Andre
AU - Tittmann, Lukas
AU - Stewart, Alexandre F.R.
AU - Shah, Svati H.
AU - Gieger, Christian
AU - Peters, Annette
AU - Rouleau, Guy A.
AU - Berger, Klaus
AU - Oexle, Konrad
AU - Di Angelantonio, Emanuele
AU - Hinds, David A.
AU - Müller-Myhsok, Bertram
N1 - Funding Information:
We thank all colleagues and staff at the participating centres of the EU-RLS-GENE consortium for their help with recruitment of patients. We thank Daniel Lam, Institute of Neurogenomics, Helmholtz Zentrum München, German Research Centre for Environmental Health, Neuherberg, Germany, for critically proofreading the draft paper. We thank the German Restless Legs Syndrome Foundation for continuously supporting our study and NIH Research Cambridge Biomedical Research Centre for funding (RG64219). JW was supported by the Deutsche Forschungsgemeinschaft (grant WI 1820/5-1). WHOe is a Hertie Senior Research Professor, supported by the Charitable Hertie Foundation. MT-L and AM were supported by the Estonian Research Council (grant IUT20-60), European Union Framework for Research and Innovation Horizon 2020 (grant 692145), European Regional Development Fund (project 2014-2020.4.01.15-0012), and the Centre of Excellence for Genomics and Translational Medicine. GMH was supported by the University of Thessaly (2845). OAR and ZW are supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke (P50 NS072187) and Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C and Sarah K Kennedy Fund for Neurodegenerative Disease Research). The DESIR study provided control genotype data for the EU-RLS-GENE genome-wide association study. We thank the INTERVAL study coordination teams, University of Cambridge, University of Oxford, and NHS Blood and Transplant (NHSBT), and the blood donation staff at the 25 static centres for help with participant recruitment and study fieldwork. We thank staff at Cambridge BioResource and NHSBT staff for their help with volunteer recruitment and members of the Cambridge BioResource Scientific Advisory Board and Management Committee for supporting this study. We also thank Brendan Burchell, University of Cambridge, for advice on restless leg syndrome in the INTERVAL study. WHOu is supported by grants to his laboratory from the National Institute for Health Research (NIHR), the European Commission (HEALTH-F2-2012-279233), the British Heart Foundation ([BHF] RP-PG-0310-1002 and RG/09/12/28096), and NHSBT, and he is a Senior Investigator for NIHR. NS is supported by the Wellcome Trust (WT098051 and WT091310) and the European Commission Framework Programme 7 (EPIGENESYS 257082 and BLUEPRINT HEALTH-F5-2011-282510). DJR is supported by NIHR (NIHR-RP-PG-0310-1004). JD is supported by BHF (SP/09/002), European Research Council (268834UK), Medical Research Council (G0800270), NIHR (BTRU-2014-10024 and Cambridge Biomedical Research Centre), and NHS Blood and Transplant (11-01-GEN). PV was supported by Progres (Q28/LF1). We thank the research participants and employees of 23andMe for making this work possible. The 23andMe research team provided infrastructure for generating 23andMe data.
Funding Information:
BS has received grants from Deutsche Forschungsgemeinschaft ([DFG] German Research Foundation) and grants from the German restless legs syndrome foundation. YD has received grants and personal fees from UCB and personal and other fees from Bioprojet and Jazz. AS has received travel grants from Habel Medizintechnik, Inspire Medical Systems, OSG, and UCB. BH has received grants and personal fees from UCB, personal fees from Abbvie, Axovant, Benevolent Bio, Janssen Cilag, Lundbeck, Mundipharma, and Ostuka, and other fees from Air Liquide Austria, Habel Medizintechnik Viena, and Vivisol Austria. WPo has received personal fees from AbbVie, AstraZeneca, BIAL, Biogen, Britannia, Cynapsus, Grünenthal, Intec, Ipsen, Lundbeck, Merz Pharmaceuticals, Novartis, Neuroderm, Orion Pharma, Prexton, Teva, UCB, and Zambon. DK has received grants from UNCE 204011/12 (Charles University Prague). WPa has received fees from GlaxoSmithKline and UCB Pharma, personal and other fees from Desitin Arzneimittel, and personal fees from Aesculap, CIN Werner Reichardt, Danish Agency for Science, Deutsches Stiftungszentrum, EBS Technologies, Kenes Israel, Klinikum Bremen-Mitte, Mundipharma, Schaaf Verlagsgesellschaft mbH, Thiel Foundation, and Thieme Verlag KG, and grants and other awards from BMBF and DFG. CT has received fees from Abbvie, Benevolent, Britannia Pharmaceuticals, Gruenenthal, Mundipharma, Servier, UCB, and Vifor Pharma. IF has received grants and personal fees from Philips and ResMed, grants from Weinmann, and personal fees from UCB. ZW has received grants from NIH/NINDS P50 NS072187, from Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C and Sarah K Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), personal fees from European Journal of Neurology and Parkinsonism and Related Disorders. ASB has received grants from British Heart Foundation, Medical Research Council, and National Institute for Health Research (NIHR), grants from Biogen, European Research Council, European Union Framework Programme 7, Merck, Novartis, and Pfizer. JD has received grants from British Heart Foundation, European Commission, European Research Council, Medical Research Council, Merck, NHS Blood and Transplant, NIHR, Novartis, Pfizer, and Wellcome Trust, and personal fees and non-financial support from Merck Sharpe and Dohme UK Atherosclerosis, Metabolic Advisory Board, Novartis Cardiovascular, and Pfizer Population Research Advisory Panel. RPA has received personal fees from Luitpold Pharma and grants from AMAG pharmaceuticals. WGO has received grants from Cybapsus, Luitpold, and Lundbeck, and speaker activities for ACADIA, Lundbeck, Neurocrine, TEVA, and UCB Pharma. JM has received personal fees from Merck Pharma, Novartis, and Takeda Pharma. KB has received unrestricted grants to the University of Muenster from Boehringer Ingelheim, German Restless Legs Society, Mundipharma Research, Neurobiotec, Roche, UCB Germany, UCB Switzerland, and Vifor Pharma. DAH is an employee of and has stock options in 23andMe. JW received grants from DFG, Else Kröner-Fresenius-Stiftung, Era Net Neuron, and German RLS Foundation, and personal fees from UCB, and has a patent pending (17 15 6438.8). Members of the 23andMe research team are employees of and have stock, stock options, or both, in 23andMe. The other authors declare no competing interests.
Publisher Copyright:
© 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
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U2 - 10.1016/S1474-4422(17)30327-7
DO - 10.1016/S1474-4422(17)30327-7
M3 - Article
C2 - 29029846
AN - SCOPUS:85031737266
VL - 16
SP - 898
EP - 907
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 11
ER -