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

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Abstract 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 localising these genetic effects to specific neural tissues. In addition, we performed the largest and most comprehensive phenome-wide association analysis of RLS to date, identifying over 100 diseases, lifestyle factors, and biomarkers significantly associated with RLS, thereby delineating its broad comorbidity spectrum. Finally, we conducted the largest brain MRI association analyses for RLS, providing further insight into how brain structure and connectivity are associated with the disorder. Together, these genome- and phenome-wide analyses clarify the genetic architecture, pathophysiology, and comorbidity landscape of restless legs syndrome.

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