Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome

Objective Restless legs syndrome (RLS) is a neurological condition that causes uncomfortable sensations in the legs and an irresistible urge to move them, typically during periods of rest. The genetic basis and pathophysiology of RLS are incompletely understood. We sought to identify additional novel genetic risk factors associated with RLS susceptibility. Methods We performed a whole‐genome sequencing and genome‐wide association meta‐analysis of RLS cases ( n = 9,851) and controls ( n = 38,957) in 3 population‐based biobanks (All of Us, Canadian Longitudinal Study on Aging, and CARTaGENE). Results Genome‐wide association analysis identified 9 independent risk loci, of which 8 had been previously reported, and 1 was a novel risk locus ( LMX1B , rs35196838, OR 1.14, 95% CI 1.09–1.19, p value = 2.2 × 10 −9 ). Furthermore, a transcriptome‐wide association study also identified GLO1 and a previously unreported gene, ELFN1 . A genetic correlation analysis revealed significant common variant overlaps between RLS and neuroticism ( r g = 0.40, se = 0.08, p value = 5.4 × 10 −7 ), depression ( r g = 0.35, se = 0.06, p value = 2.17 × 10 −8 ), and intelligence ( r g = −0.20, se = 0.06, p value = 4.0 × 10 −4 ). Interpretation Our study expands the understanding of the genetic architecture of RLS, and highlights the contributions of common variants to this prevalent neurological disorder. ANN NEUROL 2024;96:994–1005