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.

Didriksen, Nawaz, et al. identify three novel genetic risk variants for restless legs syndrome and confirm 19 out of 20 previously reported variants through a genome-wide association meta-analysis including nearly half a million individuals. Using expression QTL analysis, they also find that a subset of these loci may have a causal effect on nearby gene expression.

Details

Title
Large genome-wide association study identifies three novel risk variants for restless legs syndrome
Author
Didriksen, Maria 1   VIAFID ORCID Logo  ; Nawaz Muhammad Sulaman 2   VIAFID ORCID Logo  ; Dowsett, Joseph 3   VIAFID ORCID Logo  ; Bell, Steven 4   VIAFID ORCID Logo  ; Erikstrup Christian 5   VIAFID ORCID Logo  ; Pedersen, Ole B 6   VIAFID ORCID Logo  ; Sørensen, Erik 3 ; Jennum, Poul J 7 ; Burgdorf, Kristoffer S 3 ; Burchell, Brendan 8   VIAFID ORCID Logo  ; Butterworth, Adam S 4   VIAFID ORCID Logo  ; Soranzo, Nicole 9 ; Rye, David B 10 ; Trotti, Lynn Marie 10 ; Saini Prabhjyot 10 ; Lilja, Stefansdottir 11 ; Magnusson, Sigurdur H 11 ; Thorleifsson Gudmar 11 ; Sigmundsson Thordur 12 ; Sigurdsson, Albert P 13 ; Van Den Hurk Katja 14 ; Franke, Quee 14 ; Tanck Michael W T 15   VIAFID ORCID Logo  ; Ouwehand, Willem H 9   VIAFID ORCID Logo  ; Roberts, David J 16 ; Earley, Eric J 17   VIAFID ORCID Logo  ; Busch, Michael P 18   VIAFID ORCID Logo  ; Mast, Alan E 19 ; Page, Grier P 20   VIAFID ORCID Logo  ; Danesh, John 21 ; Emanuele, Di Angelantonio 4 ; Stefansson Hreinn 11   VIAFID ORCID Logo  ; Ullum Henrik 3 ; Stefansson Kari 11   VIAFID ORCID Logo 

1  Copenhagen University Hospital, Rigshospitalet, Department of Clinical Immunology, Copenhagen, Denmark (GRID:grid.475435.4); deCODE Genetics, Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889) 
2  deCODE Genetics, Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
3  Copenhagen University Hospital, Rigshospitalet, Department of Clinical Immunology, Copenhagen, Denmark (GRID:grid.475435.4) 
4  University of Cambridge, The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK (GRID:grid.120073.7) (ISNI:0000 0004 0622 5016) 
5  Aarhus University Hospital, Department of Clinical Immunology, Aarhus, Denmark (GRID:grid.154185.c) (ISNI:0000 0004 0512 597X) 
6  Department of Clinical Immunology, Nastved Sygehus, Nastved, Denmark (GRID:grid.154185.c) 
7  Copenhagen University Hospital, Rigshospitalet, Department of Clinical Neurophysiology, Danish Center for Sleep Medicine, Glostrup, Denmark (GRID:grid.475435.4); University of Copenhagen, Faculty of Health, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
8  University of Cambridge, Faculty of Human, Social and Political Sciences, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
9  University of Cambridge, The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Cambridge Biomedical Campus, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Department of Human Genetics, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
10  Emory University, Department of Neurology and Program in Sleep, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
11  deCODE Genetics, Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889) 
12  University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); Telemark Hospital Trust, Department of Psychiatry, Skien, Norway (GRID:grid.416950.f) (ISNI:0000 0004 0627 3771) 
13  University of Iceland, Faculty of Medicine, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
14  Sanquin Research, Department of Donor Studies, Amsterdam, The Netherlands (GRID:grid.417732.4) (ISNI:0000 0001 2234 6887) 
15  University of Amsterdam, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
16  University of Cambridge, The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Oxford, John Radcliffe Hospital, National Health Service (NHS) Blood and Transplant and Radcliffe Department of Medicine, NIHR Oxford Biomedical Research Centre, Oxford, UK (GRID:grid.5335.0); BRC Haematology Theme and Department of Haematology, Churchill Hospital, Oxford, UK (GRID:grid.415719.f) (ISNI:0000 0004 0488 9484) 
17  RTI International, Research Triangle Park, Durham, USA (GRID:grid.62562.35) (ISNI:0000000100301493) 
18  Vitalant Research Institute, San Francisco, USA (GRID:grid.62562.35); University of San Francisco, Department of Laboratory Medicine, San Francisco, USA (GRID:grid.267103.1) (ISNI:0000 0004 0461 8879) 
19  Blood Research Institute, Versiti, Milwaukee, USA (GRID:grid.280427.b) (ISNI:0000 0004 0434 015X) 
20  RTI International, Atlanta, USA (GRID:grid.62562.35) (ISNI:0000000100301493) 
21  University of Cambridge, The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, UK (GRID:grid.120073.7) (ISNI:0000 0004 0622 5016); The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Department of Human Genetics, Cambridge, UK (GRID:grid.10306.34) (ISNI:0000 0004 0606 5382) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s42003-020-01430-1
ProQuest document ID
2473250461
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.