Genetic study identifies 164 risk factors for restless leg syndrome

An international team of researchers has identified 164 genetic risk factors for restless leg syndrome, a neurological condition that affects millions of people worldwide, particularly older adults. The discovery, published in Nature Genetics, represents an eightfold expansion of previously known genetic markers and opens new pathways for diagnosis, treatment, and potentially prevention of a disorder that has long remained poorly understood despite its prevalence.

Restless leg syndrome manifests as an uncomfortable crawling or tingling sensation in the legs accompanied by an irresistible urge to move them. For some people, the symptoms appear only occasionally; for others, they strike every single night. The condition typically worsens in the evening and at night, often severely disrupting sleep. Up to one in ten older adults experience some form of the condition, though only about two to three percent develop symptoms severe enough to seek medical treatment. Yet despite affecting such a large population, the underlying causes have remained largely mysterious.

Previous research had identified 22 genetic regions associated with increased risk, but this left enormous gaps in understanding. Researchers at the Helmholtz Munich Institute of Neurogenomics, the Technical University of Munich, and the University of Cambridge pooled data from three large genome-wide association studies, creating a dataset of more than 100,000 patients and 1.5 million unaffected controls. By comparing the DNA of people with the condition to healthy individuals, they could identify genetic variations more commonly found in those with restless leg syndrome.

The analysis uncovered more than 140 previously unknown genetic risk loci, bringing the total to 164, including three on the X chromosome. Notably, the researchers found no significant genetic differences between men and women, despite the condition being twice as common in women. This suggests that the gender disparity likely stems from a complex interplay between genetic factors and environmental influences, possibly including hormonal effects.

Two of the identified genes—glutamate receptors 1 and 4—control nerve and brain function and could potentially be targeted by existing medications. Anticonvulsant drugs like perampanel and lamotrigine have already shown promise in early trials with restless leg syndrome patients, and these genetic findings could accelerate the development of new treatments. The researchers also discovered that restless leg syndrome increases the risk of developing diabetes, a connection revealed through a statistical technique called Mendelian randomization that examines cause-and-effect relationships using genetic data.

Perhaps most significantly, the expanded genetic knowledge now allows researchers to predict who will develop severe restless leg syndrome with roughly ninety percent accuracy using just three pieces of information: age, sex, and genetic markers. This capability could fundamentally shift how the condition is managed, moving from reactive treatment of symptoms to proactive identification of at-risk individuals and potentially preventing the condition from developing in the first place. While low iron levels have long been suspected as a trigger—because iron deficiency can reduce dopamine, a crucial neurotransmitter—the genetic analysis did not reveal strong links to iron metabolism, though researchers acknowledge this possibility cannot be entirely ruled out. The findings represent a watershed moment in understanding a condition that has frustrated patients and clinicians for decades.