Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
Ann Neurol. 2024 Nov;96(5):994-1005. doi: 10.1002/ana.27040. Epub 2024 Jul 30.
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.
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).
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). 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 = 0.40, se = 0.08, p value = 5.4 × 10), depression (r = 0.35, se = 0.06, p value = 2.17 × 10), and intelligence (r = -0.20, se = 0.06, p value = 4.0 × 10).
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.
不宁腿综合征（RLS）是一种神经系统疾病，会导致腿部不适和难以抑制的移动腿部的冲动，通常在休息期间发生。RLS 的遗传基础和病理生理学尚未完全了解。我们试图确定与 RLS 易感性相关的其他新的遗传风险因素。
我们对三个基于人群的生物库（All of Us、加拿大老龄化纵向研究和 CARTaGENE）中的 RLS 病例（n=9851）和对照（n=38957）进行了全基因组测序和全基因组关联荟萃分析。
全基因组关联分析确定了 9 个独立的风险位点，其中 8 个先前已报道，1 个是新的风险位点（LMX1B，rs35196838，OR 1.14，95%CI 1.09-1.19，p 值=2.2×10）。此外，转录组全基因组关联研究还鉴定了 GLO1 和一个以前未报道的基因 ELFN1。遗传相关性分析显示，RLS 与神经质（r=0.40，se=0.08，p 值=5.4×10）、抑郁（r=0.35，se=0.06，p 值=2.17×10）和智力（r=-0.20，se=0.06，p 值=4.0×10）之间存在显著的常见变异重叠。
我们的研究扩展了对 RLS 遗传结构的理解，并强调了常见变异对这种常见神经疾病的贡献。
