Genetic Clues to Restless Leg Syndrome Uncovered

Researchers have identified potential genetic markers for the etiology of restless leg syndrome, a disorder that frequently affects the elderly. The finding may make it easier to determine who is most at risk for the illness and may also suggest new treatment options.

An uncomfortable crawling sensation in the legs and a strong desire to move them can be symptoms of restless leg syndrome. While some people only infrequently experience the symptoms, others do so daily. The symptoms can significantly hinder sleep and are typically worse in the evening or at night.

Little is known about the condition’s causes, despite the fact that it affects up to 10% of older persons and that 2-3% of them are severely afflicted and seek medical attention. It is unknown why people with restless leg syndrome frequently also have additional illnesses such diabetes, hypertension, anxiety, depression, or cardiovascular diseases.

Twenty-two genetic risk loci, or areas of our genome with alterations linked to a higher chance of having the ailment, have been found in prior research. However, no recognized “biomarkers”—such as genetic signatures—can currently be utilized to make an objective diagnosis of the illness.

An international team lead by scientists from the University of Cambridge, the Helmholtz Munich Institute of Neurogenomics, and the Institute of Human Genetics at the Technical University of Munich (TUM) merged and analyzed data from three genome-wide association studies to learn more about the illness. These investigations looked for variations more frequently observed in people with restless leg syndrome by comparing the DNA of patients and healthy controls. The team’s creation of a potent dataset comprising over 1.5 million unaffected controls and over 100,000 patients was made possible by the combination of the data.

The study’s findings were released in Nature Genetics today.

The University of Cambridge’s Dr. Steven Bell, a co-author, stated: “This study is the largest of its type into this common, but poorly understood, illness. In order to improve the lives of the many millions of people affected globally, we seek to effectively manage and treat restless leg syndrome by understanding its genetic foundation.”

The group discovered more than 140 novel genetic risk loci, bringing the total known to 164—including three on the X chromosome—an eight-fold increase. Despite the illness being twice as common in women as in men, the researchers identified no significant genetic differences between the sexes. This shows that a complicated interaction between genetics and the environment, including hormones, may account for the gender inequalities we see in real life.

The scientists found that two of the genetic variations were related to genes called glutamate receptors 1 and 4, respectively, which are crucial for brain and nerve function. These may be utilized to create new treatments or as targets for currently available medications, such as anticonvulsants like lamotrigine and perampanel. Patients with restless leg syndrome have previously responded well to these medications in early trials.

In nine out of ten cases, the researchers claim it would be feasible to precisely rank who is more likely to have severe restless leg syndrome using simple data like age, sex, and genetic markers.

The researchers applied a method known as Mendelian randomization to gain an understanding of the potential impact of restless leg syndrome on general health. This investigates cause-and-effect correlations using genetic information. It was discovered that the syndrome raises the chance of getting diabetes.

Despite the fact that low blood iron levels are known to cause RLS because they can cause a decline in the neurotransmitter dopamine, the researchers were unable to identify any clear genetic associations with iron metabolism. They acknowledge that they are unable to totally rule it out as a risk factor, though.

“For the first time, we have achieved the ability to predict restless leg syndrome risk. It has been a long journey, but now we are empowered to not only treat but even prevent the onset of this condition in our patients.”- Professor Juliane Winkelmann from TUM, one of senior authors of the study

For more information: Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction, Nature Genetics, https://doi.org/10.1038/s41588-024-01763-1