New Risk Variants Identified for Restless Legs Syndrome

As many as one in ten people of European ancestry is affected by restless legs syndrome, in which sufferers feel an overwhelming urge to move, often in conjunction with unpleasant sensations, usually in the legs.

Rest and inactivity provoke the symptoms, whereas movement can lead to temporary relief. The condition is chronic and can get progressively worse, with long-lasting effects on patients' mental and physical health. People with restless legs syndrome have substantially impaired sleep, reduced overall quality of life, and increased risk of depression, anxiety disorders, hypertension, and, possibly, cardiovascular disease.

An international team of scientists led by those at German Research Centre for Environmental Health (Neuherberg, Germany) have compared the genetic data from 15,126 patients with 95, 725 controls, and identified a further 13 genetic risk variants. The findings were then replicated in a sample of 31,000 patients and 287,000 controls. The team collected diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving cases and controls of European ancestry.

The investigators performed a genome-wide association study (GWAS) and all European samples were genotyped on the Affymetrix Axiom CEU array and UK Samples were genotyped on the Affymetrix UK Biobank Axiom array. They identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals were tested for replication in an independent GWAS of 30,770 cases and 286,913 controls, followed by a joint analysis of the discovery and replication stages. They did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.

The scientists identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. Meis Homeobox 1 (MEIS1) was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1.92). Gene prioritization, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).

Steven Bell, PhD, a genetic epidemiologist and a senior co-author said, “Restless legs syndrome is surprisingly common, but despite this, we know little about what causes it and hence how to treat it. We already know that it has a strong genetic link, and this was something we wanted to explore in more detail.” The study was published on October 10, 2017, in the journal Lancet Neurology.

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German Research Centre for Environmental Health