Abstract
Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.
Original language | English |
---|---|
Article number | 703 |
Journal | Communications Biology |
Volume | 3 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2020 |
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In: Communications Biology, Vol. 3, No. 1, 703, 01.12.2020.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Large genome-wide association study identifies three novel risk variants for restless legs syndrome
AU - Didriksen, Maria
AU - Nawaz, Muhammad Sulaman
AU - Dowsett, Joseph
AU - Bell, Steven
AU - Erikstrup, Christian
AU - Pedersen, Ole B.
AU - Sørensen, Erik
AU - Jennum, Poul J.
AU - Burgdorf, Kristoffer S.
AU - Burchell, Brendan
AU - Butterworth, Adam S.
AU - Soranzo, Nicole
AU - Rye, David B.
AU - Trotti, Lynn Marie
AU - Saini, Prabhjyot
AU - Stefansdottir, Lilja
AU - Magnusson, Sigurdur H.
AU - Thorleifsson, Gudmar
AU - Sigmundsson, Thordur
AU - Sigurdsson, Albert P.
AU - Van Den Hurk, Katja
AU - Quee, Franke
AU - Tanck, Michael W.T.
AU - Ouwehand, Willem H.
AU - Roberts, David J.
AU - Earley, Eric J.
AU - Busch, Michael P.
AU - Mast, Alan E.
AU - Page, Grier P.
AU - Danesh, John
AU - Di Angelantonio, Emanuele
AU - Stefansson, Hreinn
AU - Ullum, Henrik
AU - Stefansson, Kari
N1 - Funding Information: A.E.M. received funding from Novo Nordisk. M.S.N., L.S., S.H.M., G.T., H.S., and K.S. are employees of deCODE genetics/Amgen. J.D reports grants, personal fees and nonfinancial support from Merck Sharp & Dohme (MSD), grants, personal fees and nonfinancial support from Novartis, grants from Pfizer and grants from AstraZeneca outside the submitted work. John Danesh sits on the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010); the Steering Committee of UK Biobank (since 2011); the MRC International Advisory Group (ING) member, London (since 2013); the MRC High Throughput Science ‘Omics Panel Member, London (since 2013); the Scientific Advisory Committee for Sanofi (since 2013); the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis; and the Astra Zeneca Genomics Advisory Board (2018). A.B reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis and Pfizer and personal fees from Novartis. The remaining authors have disclosed no conflicts of interest. Funding Information: We thank participants in all the included cohorts. More specifically, we thank the INTERVAL study coordination teams from Universities of Cambridge and Oxford, The NHS Blood and Transport (NHSBT), the 25 blood centers that recruited participants for this study, and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] (The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.). Similarly, we thank personnel employed in all blood banks across Denmark for making DBDS inclusion a part of their work routine. We wish to provide a thanks to Professor Richard P. Allen, Johns Hopkins University School of Medicine, Baltimore, US, for advice on identifying RLS cases among both the DBDS and the INTERVAL participants. We also express our gratitude to Dr. Simone Glynn of NHLBI for her support throughout this study, to the RBC-Omics research staff at all participating blood centers and to the testing laboratories. We thank the International EU-RLS-GENE consortium and the Cooperative Research in the Region of Augsburg (KORA) study for providing RLS-GWAS summary statistics. This study was supported with grants from The Danish Council of Independent Research—Medical Sciences (8018-00138A), The Danish Administrative Regions, The Danish Bio-and Genome bank, The Brothers Hartmann Foundation (A29659), Copenhagen University Hospital Research Foundation (Rig-shospitalets Forskningsfond). Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www. nhsbt.nhs.uk), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute of Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk/) and the NIHR Cambridge Biomedical Research Center (www.cambridge-brc.org.uk). The academic coordinating center for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (RG/13/13/30194; RG/18/ 13/33946), and NIHR Cambridge BRC (a complete list of the investigators and contributors to the INTERVAL trial is provided in reference). The Emory cohort was made possible via funds provided by individual patients, and the Arthur L. Williams Jr. and Restless Legs Syndrome foundations. Moreover, the authors acknowledge NHLBI Recipient Epidemiology and Donor Evaluation Study-III (REDS-III), which was supported by NHLBI Contracts NHLBI HHSN2682011-00001I, -00002I, -00003I, -00004I, -00005I, -00006I, -00007I, -00008I, and -00009I. Finally, the UK Biobank was financed by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government, the Northwest Regional Development Agency, the Welsh Government, British Heart Foundation, and Cancer Research UK. The UK Biobank is supported by the National Health Service (NHS). The GTEx Project is available free-of-charge to researchers, and the project is funded by the Director of the National Institutes of Health, NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. KORA was initiated and is financed by the Helmholtz Zentrum München, which is funded by the German Federal Ministry of Education and Research and by the state of Bavaria. The International EU-RLS-GENE consortium includes data from the COR study, which was supported by unrestricted grants to the University of Münster from the German Restless Legs Patient Organization (RLS Deutsche Restless Legs Vereinigung), the Swiss RLS Patient Association (Schweizerische Restless Legs Selbsthilfegruppe) and a consortium formed by Boeringer Ingelheim Pharma, Mundipharma Research, Neurobiotec, Roche Pharma, UCB (Germany + Switzerland) and Vifor Pharma. The clinical material and biospecimens of the Mayo Clinic Florida RLS collection were collected with the assistance of the Mayo Clinic internal funding through the Neuroscience Focused Research Team grant. Geno-typing of the International EU-RLS-GENE consortium dataset was supported by DFG grant 218143125 to Prof. Juliane Winkelmann. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. DBDS Genomic Consortium, responsible individuals: Andersen Steffen, Department of Finance, Copenhagen Business School, Copenhagen, Denmark. Banasik Karina, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Brunak Søren, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Burgdorf Kristoffer, Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark. Erikstrup Christian, Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark. Hansen Thomas Folkmann, Danish Headache Center, department of Neurology Rigshospitalet, Glostrup. Hjalgrim Henrik, Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. Jemec Gregor, Department of Clinical Medicine, Sealand University hospital, Roskilde, Denmark. Jen-num Poul, Department of clinical neurophysiology at University of Copenhagen, Copenhagen, Denmark. Nielsen Kasper Rene, Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark. Nyegaard Mette, Department of Biomedicine, Aarhus University, Denmark. Paarup Helene Martina, Department of Clinical Immunology, Odense University Hospital, Odense, Denmark. Pedersen Ole Birger, Department of Clinical Immunology, Naestved Hospital, Naestved. Petersen Mikkel, Department of Clinical Immunology, Aarhus University Hospital, Aarhus. Sørensen Erik, Department of Clinical Immunology, Copenhagen University Hospital Copenhagen, Denmark. Ullum Henrik, Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark. Werge Thomas, Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark. Gudbjartsson Daniel, deCODE genetics, Reykjavik, Iceland. Stefansson Kari, deCODE genetics, Reykjavik, Iceland. Stefánsson Hreinn, deCODE genetics, Reykjavik, Iceland. Þorsteinsdóttir Unnur, deCODE genetics, Reykjavik, Iceland. REDS-III, RBC-Omics STUDY GROUP MEMBERS: The NHLBI Recipient Epidemiology Donor Evaluation Study-III (REDS-III), Red Blood Cell (RBC)-Omics Study, is the responsibility of the following Hubs: Blood Research Institute, Milwaukee, WI: A.E. Mast, J.L. Gottschall, W. Bialkowski, L. Anderson, J. Miller, A. Hall, Z. Udee, V. Johnson. The Institute for Transfusion Medicine (ITXM), Pittsburgh, PA: D.J. Triulzi, J.E. Kiss, P.A. D’Andrea. University of California, San Francisco, San Francisco, CA: E.L. Murphy, A.M. Guiltinan. American Red Cross Blood Services, Farmington, CT: R.G. Cable, B.R. Spencer, S.T. Johnson. Data coordinating center: RTI International, Rockville, MD: D.J. Brambilla, M.T. Sullivan, S.M. Endres-Dighe, G.P. Page, Y. Guo, N. Haywood, D. Ringer, B.C. Siege. Central and testing laboratories: Blood Systems Research Institute, San Francisco, CA: M.P. Busch, M.C. Lanteri, M. Stone, S. Keating. Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA: T. Kanias, M. Gladwin. Steering committee chairman: University of British Columbia, Victoria, BC, Canada: S.H. Kleinman. National Heart, Lung, and Blood Institute, National Institutes of Health: S.A. Glynn, K.B. Malkin, A.M. Cristman. Finally, Muhammad S. Nawaz would also like to thank Marie Curie Initial Training Network for providing PhD funding through TS-EUROTRAIN grant (FP7-PEOPLE-2012-ITN, Grant Agr. No. 316978). Publisher Copyright: © 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.
AB - Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10−18), rs10068599-T (OR = 1.09, P = 6.9 × 10−10) and rs10769894-A (OR = 0.90, P = 9.4 × 10−14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.
UR - http://www.scopus.com/inward/record.url?scp=85096540783&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s42003-020-01430-1
DO - https://doi.org/10.1038/s42003-020-01430-1
M3 - Article
C2 - 33239738
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 703
ER -