Insights into Restless Legs Syndrome from Genome-Wide Meta-Analyses

By Daniel A. Barone, MD, FAASM, FANA

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: This genome-wide association study’s meta-analysis, performed in a large European-ancestry cohort, identified 164 risk gene loci for restless legs syndrome. Some of the loci point to potential new drug therapies, but there also was strong evidence of currently unknown environmental factors that influence the expression of various genes.

SOURCE: Schormair B, Zhao C, Bell S, et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction. Nat Genet 2024;56:1090-1099.

Restless legs syndrome (RLS) is a common disorder affecting up to 10% of older adults. It is characterized by an unrelenting urge to move the legs, usually occurring at night, when patients are lying down to sleep. These urges prevent the onset of sleep owing to a feeling of needing to move or walk during times of rest.

Unfortunately, patients with RLS may experience delayed diagnosis and insufficient treatment. To advance disease prediction and find new avenues for therapy, Schormair et al performed a meta-analysis of genome-wide association studies (GWAS) in 116,647 individuals with RLS (cases) vs. 1,546,466 controls of European ancestry.

Three cohorts were included, ranging from in-person interviews to a single online question. Previous GWAS identified 22 risk loci for RLS, but this current study increased that number eightfold to 164, including three on chromosome X. The use of locus annotation prioritized genes that may identify patients who are suitable for personalized medication, such as the glutamate receptors 1 and 4. Additionally, Mendelian randomization studies indicated that RLS may be a causal risk factor for diabetes.

Sex-specific genetic susceptibility in RLS also was investigated. While the heritability was significantly higher in women, the genetic correlation between the sexes was close to one, thought to be the result of an unobserved environmental risk factor and corresponding gene-environment interactions driving the difference in heritability. The authors noted that with larger sample sizes, some of these may turn out to be true sex-specific association signals.

Through these meta-analyses, potential targets for drug development have been uncovered and causal relationships between RLS and relevant comorbidities and risk factors have been identified. This study marks a substantial advance in deciphering the genetic basis of RLS and paves the way for improving treatment and prevention strategies.

COMMENTARY

This study is extremely important to multiple fields in medicine, including general neurology, movement disorders, and sleep medicine. At a minimum, it highlights the complexity of the RLS phenotype, but, more importantly, it opens the window to advancing understanding and treatment of a very disabling and confounding condition.

However, as the authors point out, there were several limitations. First, there is a paucity of biobank-scale longitudinal datasets featuring high-quality RLS phenotyping and detailed medical and socioeconomic information; these data are required to thoroughly investigate the potential relationships discovered by genetic correlation. Second, large-scale GWAS for RLS currently are limited to populations of European ancestry, and an extension to non-European populations is imperative. Regardless of these limitations, this study and other contemporary GWAS are advancing the understanding of RLS.

For example, another recent GWAS of individuals of European ancestry (n = 10,257 cases; 470,725 controls) found a hereditary inclination toward attention-deficit hyperactivity disorder, potentially augmenting susceptibility to RLS.¹ The fact that no genetic association exists points to another biological link or exposure to the same environmental or lifestyle factors.

There is great complexity in the RLS phenotype, insofar as the expression of the disease is influenced by numerous genetic factors. This study also points out the important effects of environmental factors on the expressions of genetic susceptibilities. The current study is a very profound step forward in understanding the genetic basis for RLS and paving the way for more targeted therapeutic interventions, which are sorely needed.

REFERENCE

1. Xiao G, Shi H, Lan Q, et al. Association among attention-deficit hyperactivity disorder, restless legs syndrome, and peripheral iron status: A two-sample Mendelian randomization study. Front Psychiatry 2024;15:1310259.