Scientists have discovered genetic clues to the cause of restless legs syndrome, a common condition among elderly people. The finding could help identify individuals at greatest risk of the disease and point to potential ways to treat it.
The results of the study were published today on Nature Genetics.
How to treat restless legs syndrome
Restless legs syndrome can cause an unpleasant tingling sensation in the legs and an uncontrollable urge to move them. Some people experience symptoms only occasionally, while others experience them every day. Symptoms usually worsen in the evening or at night and can severely affect sleep.
Although the condition is 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 suffer from other conditions, such as depression or anxiety, cardiovascular disorders, high blood pressure, and diabetes, but the reason is not known.
Previous studies have identified 22 genetic risk loci, which are regions of our genome that contain changes associated with an increased risk of developing the condition. But there are still no known biomarkers, such as genetic signatures, that could be used to objectively diagnose the condition.
To further explore the condition, an international team led by researchers from the Helmholtz Institute for Neurogenomics in Munich, the Institute of Human Genetics at the Technical University of Munich (TUM) and the University of Cambridge brought together and analyzed data from three Genome-wide association studies.
These studies compared the DNA of patients and healthy controls to look for differences most commonly found in people with restless legs syndrome. By combining the data, the team was able to create a powerful dataset with more than 100,000 patients and more than 1.5 million unaffected controls.
Co-author Dr Steven Bell from the University of Cambridge said: “This study is the largest of its kind on this common, but poorly understood condition. 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 around the world.”
The team identified more than 140 new genetic risk loci, increasing the known number eightfold 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 and men.
This suggests that a complex interaction between genetics and environment (including hormones) may explain the gender differences we observe in real life.
Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4, which are important for nerve and brain function, respectively. These could potentially be targeted by existing drugs, such as anticonvulsants such as perampanel and lamotrigine, or used to develop new drugs. Early studies 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 such as age, sex and genetic markers to accurately classify who is most likely to have severe restless legs syndrome in nine out of ten cases.
To understand how restless legs syndrome might affect overall health, the researchers used a technique called 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 drop in the neurotransmitter dopamine, researchers have not found strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.
Professor Juliane Winkelmann from TUM, one of the senior authors of the study, said: “For the first time, we have achieved the ability to predict the risk of restless legs syndrome. It has been a long journey, but we now have the power to not only treat but also prevent the onset of this condition in our patients.”
Restless legs syndrome study identifies 13 new genetic risk variants
A new study into the genetics underlying restless legs syndrome has identified 13 previously unknown genetic risk variants, while helping to define potential new treatment options for the condition.
Around one in ten people of European descent are affected by restless legs syndrome, in which sufferers feel an overwhelming need to move, often in conjunction with unpleasant sensations, usually in the legs. Rest and inactivity cause symptoms, while movement can lead to temporary relief. The condition is chronic and can progressively worsen, with long-term effects on patients’ mental and physical health.
People with restless legs syndrome have substantially impaired sleep, reduced overall quality of life, and an increased risk of depression, anxiety disorders, hypertension, and possibly cardiovascular disease.
For about one in 50 people, the condition may be serious enough to require chronic medications, which in turn can have potentially serious side effects.
Family and twin studies have shown that there is a strong genetic component to the disorder and have led to the discovery of six genetic variants that increase the risk of developing the condition.
“We have been studying the genetics of restless legs syndrome for more than 10 years and the current study is the largest conducted to date,” says Dr. Barbara Schormair from the Institute for Neurogenomics at Helmholtz Zentrum München, first author of the study . “We are convinced that the newly discovered risk loci will contribute substantially to our understanding of the causal biology of the disease.”
Now, an international team of researchers has compared genetic data from more than 15,000 patients with more than 95,000 controls and identified 13 additional genetic risk variants. The results were then replicated in a sample of 31,000 patients and 287,000 controls. The results are published in Lancet Neurology.
“Restless legs syndrome is surprisingly common, but despite this, we know little about its causes and therefore how to treat it,” says Dr. Steven Bell of the University of Cambridge’s Department of Public Health and Primary Care, also one of the study’s first authors. “We already know that it has a strong genetic link, and this was something we wanted to explore in more detail.”
Many of the genetic variants have previously been linked to the growth and development of nerve cells – a process known as neurogenesis – and changes in the formation of neuronal circuits. These findings strengthen the case that restless legs syndrome is a neurodevelopmental disorder whose origins may date back to development in the womb and reduced growth of nerve cells in later life.
“The genetic risk variants that we have discovered give more weight to the idea that this condition is linked to the development of our nervous system,” says Dr. Emanuele Di Angelantonio, also from the Department of Public Health and Primary Care. “It also gives us some clues about how we can treat patients with this condition.”
Professor Juliane Winkelmann, director of the Institute for Neurogenomics at the Helmholtz Zentrum and of an outpatient clinic for restless legs syndrome at the Klinikum Rechts der Isar in Munich, adds: “Our genetic results represent an important step towards development of new and improved treatment options for our patients.”
A particular biological pathway implicated by the findings is known to be a target for the drug thalidomide. Although the drug has a controversial reputation due to its previous use in treating pregnant women leading to serious birth defects in their offspring, it is now used to treat some cancers.
The researchers suggest that thalidomide or similar drugs may offer potential treatment options for male patients with restless legs syndrome and for female patients beyond reproductive age, but they emphasize the need for rigorous clinical trials for efficacy and side effects before any use.
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