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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 (\n                    <jats:italic>r<\/jats:italic>\n                    <jats:sub>g<\/jats:sub>\n                    \u2009=\u20090.96). 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)\u2009=\u20090.82\u20130.91). 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.\n                  <\/jats:p>","DOI":"10.1038\/s41588-024-01763-1","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T06:03:42Z","timestamp":1717567422000},"page":"1090-1099","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk 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J.W., B.S., K.O. and C.Z. have filed a patent application (WO2021185936A1). Z.K.W. serves as PI or co-PI on Biohaven Pharmaceuticals (BHV4157-206), Neuraly (NLY01-PD-1) and Vigil Neuroscience (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and CSF1R biomarker and repository project) grants. Z.K.W. serves as co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for Vigil Neuroscience. W.P. has received honoraria as a speaker from Philips and MediPark Clinic and as a consultant from Abbott and Precisis. J. Danesh serves on scientific advisory boards for AstraZeneca, Novartis and the UK Biobank and has received multiple grants from academic, charitable and industry sources outside of the submitted work. A.S.B. reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron and Sanofi. D.A.H., N.A.F., P.N. and members of the 23andMe Research Team are employed by and hold stock or stock options in 23andMe. Authors affiliated with deCODE Genetics\/Amgen declare competing financial interests as employees. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}