Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

1st Faculty of Medicine Charles University Prague Prague Czech Republic

Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague Pilsen Czech Republic

Bragée ME CFS Center Stockholm Sweden

British Heart Foundation Cardiovascular Epidemiology Unit Department of Public Health and Primary Care University of Cambridge Cambridge UK

British Heart Foundation Centre of Research Excellence University of Cambridge Cambridge UK

Cancer Research UK Cambridge Institute Li Ka Shing Centre University of Cambridge Cambridge UK

Center for Restless Legs Syndrome Department of Neurology Johns Hopkins University Baltimore MD USA

Centre d'Études Avancées en Médecine du Sommeil Hôpital du Sacré Cœur de Montréal Montreal Quebec Canada

Chair of Epidemiology Institute for Medical Information Processing Biometry and Epidemiology Medical Faculty Ludwig Maximilians Universität München Munich Germany

Clinical and Molecular Metabolism Research Program Faculty of Medicine University of Helsinki Helsinki Finland

Department of Clinical Immunology Aalborg University Hospital Aalborg Denmark

Department of Clinical Immunology Aarhus University Hospital Aarhus Denmark

Department of Clinical Immunology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Clinical Immunology Odense University Hospital Odense Denmark

Department of Clinical Immunology Zealand University Hospital Køge Denmark

Department of Clinical Medicine Aarhus University Aarhus Denmark

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Genetic Epidemiology Institute for Human Genetics University of Münster Münster Germany

Department of Haematology and BRC Haematology Theme Churchill Hospital Headington Oxford UK

Department of Haematology University College London Hospitals London UK

Department of Haematology University of Cambridge Cambridge UK

Department of Human Genetics McGill University Montreal Quebec Canada

Department of Human Genetics the Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton UK

Department of Medicine Duke University School of Medicine Durham NC USA

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Science of Czech Republic Prague Czech Republic

Department of Neurology and Centre of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology and Neurosurgery McGill University Montreal Quebec Canada

Department of Neurology Emory University Atlanta GA USA

Department of Neurology Ludwig Maximilians University Munich Munich Germany

Department of Neurology Mayo Clinic Jacksonville FL USA

Department of Neurology Methodist Neurological Institute Weill Cornell Medical School Houston TX USA

Department of Neurology Nicosia General Hospital Medical School University of Cyprus Nicosia Cyprus

Department of Neurology Philipps University Marburg Marburg Germany

Department of Neurology University Medical Center Göttingen Göttingen Germany

Department of Neuroscience Mayo Clinic College of Medicine Jacksonville FL USA

Department of Neuroscience University of Copenhagen Copenhagen Denmark

Department of Neurosciences Université de Montréal Montreal Quebec Canada

Department of Neurosurgery University Medical Center Göttingen Göttingen Germany

Department of Oncology University of Cambridge Cambridge UK

Department of Public Health and Welfare National Institute for Health and Welfare Helsinki Finland

Department of Pulmonology Center of Sleep Medicine Charité Universitätsmedizin Berlin Berlin Germany

Duke Clinical Research Institute Duke University School of Medicine Durham NC USA

eCODE Genetics Amgen Reykjavik Iceland

Estonian Genome Center Institute of Genomics University of Tartu Tartu Estonia

German Center for Mental Health partner site Munich Augsburg Munich Augsburg Germany

German Research Center for Cardiovascular Disease partner site Munich Heart Alliance Hannover Germany

Health Data Research UK Cambridge Wellcome Genome Campus and University of Cambridge Cambridge UK

Health Data Science Research Centre Fondazione Human Technopole Milan Italy

Institute of Clinical Molecular Biology Kiel University Kiel Germany

Institute of Epidemiology and Social Medicine University of Münster Münster Germany

Institute of Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Institute of Human Genetics TUM School of Medicine and Health Technical University of Munich Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre University of Ottawa Heart Institute Ottawa Ontario Canada

L'institut du thorax CNRS INSERM Nantes Université Nantes France

Magdalene College Cambridge UK

Me Inc Sunnyvale CA USA

Munich Cluster for Systems Neurology Munich Germany

National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour University of Cambridge Cambridge UK

Neurogenetic Systems Analysis Group Institute of Neurogenomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Neuropsychiatry Centre Erding München Erding Germany

NHS Blood and Transplant Cambridge Biomedical Campus Cambridge UK

Paracelsus Elena Klinik Kassel Germany

PopGen Biobank and Institute of Epidemiology Christian Albrechts University Kiel Kiel Germany

Radcliffe Department of Medicine and National Health Service Blood and Transplant Oxford UK

Research Unit of Molecular Epidemiology Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Sleep Disorders Clinic Department of Neurology Medical University of Innsbruck Innsbruck Austria

Sleep Wake Disorders Center Department of Neurology Hôpital Gui de Chauliac CHU Montpellier Institut des Neurosciences de Montpellier INSERM Université de Montpellier Montpellier France

SomnoDiagnostics Osnabrück Germany

Statens Serum Institute Copenhagen Denmark

The Neuro McGill University Montreal Quebec Canada

Victor Phillip Dahdaleh Heart and Lung Research Institute University of Cambridge Cambridge UK

Zobrazit více v PubMed

Allen RP, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101–119. PubMed

Manconi M, et al. Restless legs syndrome. Nat. Rev. Dis. Primers. 2021;7:80. PubMed

Schormair B, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol. 2017;16:898–907. PubMed PMC

Didriksen M, et al. Large genome-wide association study identifies three novel risk variants for restless legs syndrome. Commun. Biol. 2020;3:703. PubMed PMC

Allen RP, et al. Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med. 2014;15:860–873. PubMed

Trenkwalder C, et al. Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol. 2018;17:994–1005. PubMed

Trenkwalder C, Allen R, Hogl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology. 2016;86:1336–1343. PubMed PMC

Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch. Intern. Med. 2004;164:196–202. PubMed

Pantaleo NP, Hening WA, Allen RP, Earley CJ. Pregnancy accounts for most of the gender difference in prevalence of familial RLS. Sleep Med. 2010;11:310–313. PubMed PMC

Schormair B, et al. PTPRD (protein tyrosine phosphatase receptor type δ) is associated with restless legs syndrome. Nat. Genet. 2008;40:946–948. PubMed

Akcimen F, et al. Transcriptome-wide association study for restless legs syndrome identifies new susceptibility genes. Commun. Biol. 2020;3:373. PubMed PMC

Sarayloo F, et al. SKOR1 has a transcriptional regulatory role on genes involved in pathways related to restless legs syndrome. Eur. J. Hum. Genet. 2020;28:1520–1528. PubMed PMC

Tilch E, et al. Identification of restless legs syndrome genes by mutational load analysis. Ann. Neurol. 2020;87:184–193. PubMed

Moran TH, Robinson PH, Goldrich MS, McHugh PR. Two brain cholecystokinin receptors: implications for behavioral actions. Brain Res. 1986;362:175–179. PubMed

Bernard A, et al. The cholecystokinin type 2 receptor, a pharmacological target for pain management. Pharmaceuticals. 2021;14:1185. PubMed PMC

Burkhart A, et al. Expression of iron-related proteins at the neurovascular unit supports reduction and reoxidation of iron for transport through the blood–brain barrier. Mol. Neurobiol. 2016;53:7237–7253. PubMed

Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of mammalian iron metabolism. Cell. 2010;142:24–38. PubMed

Girelli D, Ugolini S, Busti F, Marchi G, Castagna A. Modern iron replacement therapy: clinical and pathophysiological insights. Int. J. Hematol. 2018;107:16–30. PubMed

Wang C, et al. Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging. Nat. Neurosci. 2022;25:818–831. PubMed PMC

Bell S, et al. A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis. Commun. Biol. 2021;4:156. PubMed PMC

Elliott LT, et al. Genome-wide association studies of brain imaging phenotypes in UK Biobank. Nature. 2018;562:210–216. PubMed PMC

Jansen PR, et al. Genome-wide analysis of insomnia in 1,331,010 individuals identifies new risk loci and functional pathways. Nat. Genet. 2019;51:394–403. PubMed

Lane JM, et al. Biological and clinical insights from genetics of insomnia symptoms. Nat. Genet. 2019;51:387–393. PubMed PMC

Connor JR, Patton SM, Oexle K, Allen RP. Iron and restless legs syndrome: treatment, genetics and pathophysiology. Sleep Med. 2017;31:61–70. PubMed PMC

Hametner S, et al. The influence of brain iron and myelin on magnetic susceptibility and effective transverse relaxation—a biochemical and histological validation study. Neuroimage. 2018;179:117–133. PubMed

Ravanfar P, et al. Systematic review: quantitative susceptibility mapping (QSM) of brain iron profile in neurodegenerative diseases. Front. Neurosci. 2021;15:618435. PubMed PMC

Garcia-Borreguero D, Cano I, Granizo JJ. Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel. Sleep Med. 2017;34:105–108. PubMed

Youssef EA, Wagner ML, Martinez JO, Hening W. Pilot trial of lamotrigine in the restless legs syndrome. Sleep Med. 2005;6:89. PubMed

Winkelmann J, et al. Treatment of restless legs syndrome: evidence-based review and implications for clinical practice (revised 2017) Mov. Disord. 2018;33:1077–1091. PubMed

Casello SM, et al. Neuropeptide system regulation of prefrontal cortex circuitry: implications for neuropsychiatric disorders. Front. Neural Circuits. 2022;16:796443. PubMed PMC

Ning P, Mu X, Yang X, Li T, Xu Y. Prevalence of restless legs syndrome in people with diabetes mellitus: a pooling analysis of observational studies. eClinicalMedicine. 2022;46:101357. PubMed PMC

Darrous L, Mounier N, Kutalik Z. Simultaneous estimation of bi-directional causal effects and heritable confounding from GWAS summary statistics. Nat. Commun. 2021;12:7274. PubMed PMC

Di Angelantonio E, et al. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors. Lancet. 2017;390:2360–2371. PubMed PMC

Finan C, et al. The druggable genome and support for target identification and validation in drug development. Sci. Transl. Med. 2017;9:eaag1166. PubMed PMC

Astle WJ, et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell. 2016;167:1415–1429. PubMed PMC

Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191. PubMed PMC

Zhou W, et al. Efficiently controlling for case–control imbalance and sample relatedness in large-scale genetic association studies. Nat. Genet. 2018;50:1335–1341. PubMed PMC

Baselmans BML, et al. Multivariate genome-wide analyses of the well-being spectrum. Nat. Genet. 2019;51:445–451. PubMed

Han B, Eskin E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am. J. Hum. Genet. 2011;88:586–598. PubMed PMC

Chang CC, et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. PubMed PMC

Yang J, et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 2012;44:369–375. PubMed PMC

Bulik-Sullivan BK, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 2015;47:291–295. PubMed PMC

Speed D, Holmes J, Balding DJ. Evaluating and improving heritability models using summary statistics. Nat. Genet. 2020;52:458–462. PubMed

Lee JJ, et al. Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. Nat. Genet. 2018;50:1112–1121. PubMed PMC

Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9:559. PubMed PMC

Hemani G, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018;7:e34408. PubMed PMC

Pers TH, et al. Biological interpretation of genome-wide association studies using predicted gene functions. Nat. Commun. 2015;6:5890. PubMed PMC

Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 2017;8:1826. PubMed PMC

de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput. Biol. 2015;11:e1004219. PubMed PMC

Barbeira AN, et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat. Commun. 2018;9:1825. PubMed PMC

Barbeira AN, et al. Integrating predicted transcriptome from multiple tissues improves association detection. PLoS Genet. 2019;15:e1007889. PubMed PMC

Hormozdiari F, et al. Colocalization of GWAS and eQTL signals detects target genes. Am. J. Hum. Genet. 2016;99:1245–1260. PubMed PMC

Chen W, McDonnell SK, Thibodeau SN, Tillmans LS, Schaid DJ. Incorporating functional annotations for fine-mapping causal variants in a Bayesian framework using summary statistics. Genetics. 2016;204:933–958. PubMed PMC

Timshel PN, Thompson JJ, Pers TH. Genetic mapping of etiologic brain cell types for obesity. eLife. 2020;9:e55851. PubMed PMC

Finucane HK, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 2015;47:1228–1235. PubMed PMC

Skene NG, et al. Genetic identification of brain cell types underlying schizophrenia. Nat. Genet. 2018;50:825–833. PubMed PMC

Prive F, Arbel J, Vilhjalmsson BJ. LDpred2: better, faster, stronger. Bioinformatics. 2021;36:5424–5431. PubMed PMC

LeDell, E. & Poirier, S. H2O AutoML: scalable automatic machine learning. In 7th ICML Workshop on Automated Machine Learning (ICML, 2020).

Paszke, A. et al. PyTorch: an imperative style, high-performance deep learning library. In Proc. 33rd International Conference on Neural Information Processing Systems 721 (Curran Associates, 2019).

Schormair, B. et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology, and risk prediction - additional data and code. Zenodo10.5281/zenodo.10804907 (2024). PubMed PMC

Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction