Genetic Clues Unlock Mysteries of Restless Legs Syndrome

Summary: A study has identified over 140 new genetic risk factors for restless legs syndrome, increasing the total to 164. This discovery enhances understanding of the condition’s genetic basis, potentially leading to better diagnosis, management, and treatment. The findings highlight possible drug targets and the role of genetics and environment in the condition.

Key Takeaways:

Researchers identified over 140 new genetic risk loci for restless legs syndrome, significantly expanding the known genetic factors.
The study highlights genes related to nerve and brain function that could be targeted by existing drugs or used to develop new treatments.
Researchers say the genetic markers combined with basic information like age and sex can accurately predict the likelihood of severe restless legs syndrome in nine out of 10 cases.

Scientists have discovered genetic clues to the cause of restless legs syndrome.

They say the discovery could help identify those individuals at greatest risk of the condition and point to potential ways to treat it.

Despite the condition being relatively common—up to one in 10 older adults experience symptoms, while 2-3% are severely affected and seek medical help—little is known about its causes. People with restless legs syndrome often have other conditions, such as depression or anxiety, cardiovascular disorders, hypertension, and diabetes, but the reason why is not known.

Previous studies had identified 22 genetic risk loci—that is, regions of our genome that contain changes associated with increased risk of developing the condition. But there are still no known “biomfarkers,” such as genetic signatures, that could be used to objectively diagnose the condition.

To explore the condition further, an international team led by researchers at the Helmholtz Munich Institute of Neurogenomics, the Institute of Human Genetics of the Technical University of Munich, and the University of Cambridge pooled and analyzed data from three genome-wide association studies. These studies compared the DNA of patients and healthy controls to look for differences more commonly found in those with restless legs syndrome. By combining the data, the team was able to create a powerful dataset with more than 100,000 patients and over 1.5 million unaffected controls.

The results of the study are published in Nature Genetics.

Study Results and Genetic Findings

“This study is the largest of its kind into this common but poorly understood condition,” says co-author Steven Bell, PhD, from the University of Cambridge, in a release. “By understanding the genetic basis of restless legs syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide.”

The team identified over 140 new genetic risk loci, increasing the number known eight-fold to 164, including three on the X chromosome. The researchers found no strong genetic differences between men and women, despite the condition being twice as common in women as it is men. This suggests that a complex interaction of genetics and the environment (including hormones) may explain the gender differences we observe in real life.

Potential Drug Targets and Treatment Implications

Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4, respectively, which are important for nerve and brain function. These could potentially be targeted by existing drugs, such as anticonvulsants like perampanel and lamotrigine, or used to develop new drugs. Early trials have already shown positive responses to these drugs in patients with restless legs syndrome.

The researchers say it would be possible to use basic information like age, sex, and genetic markers to accurately rank who is more likely to have severe restless legs syndrome in nine cases out of 10.

Health Impacts and Further Research

To understand how restless legs syndrome might affect overall health, the researchers used Mendelian randomization. This uses genetic information to examine cause-and-effect relationships. It revealed that the syndrome increases the risk of developing diabetes.

Although low levels of iron in the blood are thought to trigger restless legs syndrome—because they can lead to a fall in the neurotransmitter dopamine—the researchers did not find strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.

Conclusions and Future Directions

Professor Juliane Winkelmann from the Institute of Human Genetics of the Technical University of Munich, one of the senior authors of the study, adds in a release, “For the first time, we have achieved the ability to predict restless legs 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 Emanuele Di Angelantonio, a co-author of the study and director of the National Institute for Health Research and NHS Blood and Transplant-funded Research Unit in Blood Donor Health and Behavior, says in a release, “Given that low iron levels are thought to trigger restless legs syndrome, we were surprised to find no strong genetic links to iron metabolism in our study. It may be that the relationship is more complex than we initially thought, and further work is required.”

The dataset included the INTERVAL study of England’s blood donors in collaboration with NHS Blood and Transplant.