Large-scale genome- and phenome-wide analyses reveal the genetic architecture, pathophysiology and comorbidity of restless legs syndrome

Restless legs syndrome (RLS) is a common sleep-related movement disorder, affecting approximately 4% of adults worldwide, with a substantially higher prevalence in individuals of European ancestry, reaching 5-13%. However, its genetic architecture and pathophysiology remain poorly understood. Here, we conducted a large-scale meta-analysis of more than 1.3 million individuals of European ancestry to explored the shared and ancestry-specific genetic architectures of RLS. We performed the first genome-wide association analyses of RLS in the UK Biobank and All of Us cohorts, leading to the identification of 15 novel RLS-associated loci. Using an updated variant-to-gene mapping and enrichment framework, we linked RLS risk signals to coherent neurodevelopmental and synaptic programs, with spatial transcriptomics analyses further localizing these genetic effects to specific neural tissues. In addition, we performed the largest and most comprehensive phenome-wide association analysis of RLS to