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

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Large genome-wide association study identifies three novel risk variants for restless legs syndrome
Communications Biology ( IF 5.2 ) Pub Date : 2020-11-25 , DOI: 10.1038/s42003-020-01430-1
Maria Didriksen _{1,

2} , Muhammad Sulaman Nawaz _{2,

3} , Joseph Dowsett ₁ , Steven Bell _{4,

5,

6} , Christian Erikstrup ₇ , Ole B Pedersen ₈ , Erik Sørensen ₁ , Poul J Jennum _{9,

10} , Kristoffer S Burgdorf ₁ , Brendan Burchell ₁₁ , Adam S Butterworth _{4,

5,

6} , Nicole Soranzo _{4,

12,

13} , David B Rye ₁₄ , Lynn Marie Trotti ₁₄ , Prabhjyot Saini ₁₄ , Lilja Stefansdottir ₂ , Sigurdur H Magnusson ₂ , Gudmar Thorleifsson ₂ , Thordur Sigmundsson _{3,

15} , Albert P Sigurdsson ₃ , Katja Van Den Hurk ₁₆ , Franke Quee ₁₆ , Michael W T Tanck ₁₇ , Willem H Ouwehand _{4,

12,

13} , David J Roberts _{4,

18,

19} , Eric J Earley ₂₀ , Michael P Busch _{21,

22} , Alan E Mast ₂₃ , Grier P Page ₂₄ , John Danesh _{4,

5,

6,

13} , Emanuele Di Angelantonio _{4,

5,

6} , Hreinn Stefansson ₂ , Henrik Ullum ₁ , Kari Stefansson ₂

Affiliation

Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, 2100, Copenhagen, Denmark.
deCODE Genetics, 101, Reykjavik, Iceland.
Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
The National Institute for Health Research Blood and Transplant Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB1 8RN, UK.
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Immunology, Nastved Sygehus, Nastved, Denmark.
Department of Clinical Neurophysiology, Danish Center for Sleep Medicine, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
Faculty of Health, University of Copenhagen, Copenhagen, Denmark.
Faculty of Human, Social and Political Sciences, University of Cambridge, Cambridge, CB1 8RN, UK.
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0PT, UK.
Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
Department of Neurology and Program in Sleep, Emory University, Atlanta, GA, USA.
Department of Psychiatry, Telemark Hospital Trust, Skien, Norway.
Department of Donor Studies, Sanquin Research, 1066 CX, Amsterdam, The Netherlands.
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
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.
BRC Haematology Theme and Department of Haematology, Churchill Hospital, Oxford, UK.
RTI International, Research Triangle Park, Durham, NC, USA.
Vitalant Research Institute, San Francisco, CA, USA.
Department of Laboratory Medicine, University of San Francisco, San Francisco, CA, USA.
Blood Research Institute, Versiti, Milwaukee, WI, USA.
RTI International, Atlanta, GA, USA.

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.

中文翻译：

大型全基因组关联研究确定了不宁腿综合征的三种新风险变异

不宁腿综合征 (RLS) 是一种常见的神经感觉运动障碍，通常被描述为与移动腿部冲动相关的不愉快感觉。在此，我们报告了 RLS 全基因组关联研究的荟萃分析结果，其中包括 480,982 名白种人（病例 = 10,257 例）和 24,977 例后续样本（病例 = 6,651 例）。我们确认了先前报告的 20 个 RLS 序列变异中 19 个位点的 19 个，并报告了三个新的 RLS 关联； rs112716420-G（OR=1.25， P =1.5× ¹⁰⁻¹⁸ ），rs10068599-T（OR=1.09， P =6.9× ¹⁰⁻¹⁰ ）和rs10769894-A（OR=0.90， P =9.4× ¹⁰⁻¹⁴ ）。在 22 个 RLS 位点中的 4 个，cis-eQTL 分析表明对基因表达的因果影响。通过 RLS 的多基因风险评分，我们扩展了先前的流行病学发现，表明肥胖、吸烟和大量饮酒是 RLS 的危险因素。为了提高我们的理解，以寻求更好的治疗方法，需要进行更多的遗传学研究，以对疾病生物学产生更深入的了解。

更新日期：2020-11-25

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