Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Maria Didriksen; Muhammad Sulaman Nawaz; Joseph Dowsett; Steven Bell; Christian Erikstrup; Ole B Pedersen; Erik Sørensen; Poul J Jennum; Kristoffer S Burgdorf; Brendan Burchell; Adam S Butterworth; Nicole Soranzo; David B Rye; Lynn Marie Trotti; Prabhjyot Saini; Lilja Stefansdottir; Sigurdur H Magnusson; Gudmar Thorleifsson; Thordur Sigmundsson; Albert P Sigurdsson; Katja Van Den Hurk; Franke Quee; Michael W T Tanck; Willem H Ouwehand; David J Roberts; Eric J Earley; Michael P Busch; Alan E Mast; Grier P Page; John Danesh; Emanuele Di Angelantonio; Hreinn Stefansson; Henrik Ullum; Kari Stefansson

doi:10.1038/s42003-020-01430-1

Large genome-wide association study identifies three novel risk variants for restless legs syndrome

Commun Biol. 2020 Nov 25;3(1):703. doi: 10.1038/s42003-020-01430-1.

Authors

Maria Didriksen^{1

2}, Muhammad Sulaman Nawaz^{2

3}, Joseph Dowsett¹, Steven Bell^{4

5

6}, Christian Erikstrup⁷, Ole B Pedersen⁸, Erik Sørensen¹, Poul J Jennum^{9

10}, Kristoffer S Burgdorf¹, Brendan Burchell¹¹, Adam S Butterworth^{4

5

6}, Nicole Soranzo^{4

12

13}, David B Rye¹⁴, Lynn Marie Trotti¹⁴, Prabhjyot Saini¹⁴, Lilja Stefansdottir², Sigurdur H Magnusson², Gudmar Thorleifsson², Thordur Sigmundsson^{3

15}, Albert P Sigurdsson³, Katja Van Den Hurk¹⁶, Franke Quee¹⁶, Michael W T Tanck¹⁷, Willem H Ouwehand^{4

12

13}, David J Roberts^{4

18

19}, Eric J Earley²⁰, Michael P Busch^{21

22}, Alan E Mast²³, Grier P Page²⁴, John Danesh^{4

5

6

13}, Emanuele Di Angelantonio^{4

5

6}, Hreinn Stefansson², Henrik Ullum²⁵, Kari Stefansson²

Affiliations

¹ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
² deCODE Genetics, 101, Reykjavik, Iceland.
³ Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
⁴ The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
⁵ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
⁶ British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
⁷ Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
⁸ Department of Clinical Immunology, Nastved Sygehus, Nastved, Denmark.
⁹ Department of Clinical Neurophysiology, Danish Center for Sleep Medicine, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
¹⁰ Faculty of Health, University of Copenhagen, Copenhagen, Denmark.
¹¹ Faculty of Human, Social and Political Sciences, University of Cambridge, Cambridge, CB1 8RN, UK.
¹² Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK.
¹³ Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
¹⁴ Department of Neurology and Program in Sleep, Emory University, Atlanta, GA, USA.
¹⁵ Department of Psychiatry, Telemark Hospital Trust, Skien, Norway.
¹⁶ Department of Donor Studies, Sanquin Research, 1066 CX, Amsterdam, The Netherlands.
¹⁷ Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
¹⁸ National Health Service (NHS) Blood and Transplant and Radcliffe Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, Oxford, UK.
¹⁹ BRC Haematology Theme and Department of Haematology, Churchill Hospital, Oxford, UK.
²⁰ RTI International, Research Triangle Park, Durham, NC, USA.
²¹ Vitalant Research Institute, San Francisco, CA, USA.
²² Department of Laboratory Medicine, University of San Francisco, San Francisco, CA, USA.
²³ Blood Research Institute, Versiti, Milwaukee, WI, USA.
²⁴ RTI International, Atlanta, GA, USA.
²⁵ Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark. henrik.ullum@regionh.dk.

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Genetic Predisposition to Disease* / epidemiology
Genetic Predisposition to Disease* / genetics
Genome-Wide Association Study
Humans
Linkage Disequilibrium
Middle Aged
Polymorphism, Single Nucleotide / genetics*
Restless Legs Syndrome* / epidemiology
Restless Legs Syndrome* / genetics

Abstract

Publication types

MeSH terms

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