Scientists have discovered genetic clues to the cause of restless legs syndrome, a condition that often occurs in older adults. The discovery could help identify those at greatest risk of developing the condition and suggest possible ways to treat it.

Restless legs Syndrome is Widespread

Restless legs syndrome can cause an uncomfortable tingling sensation in the legs and an overwhelming urge to move them ,For some people the symptoms only occur occasionally, while for others they occur daily. Symptoms are usually worse in the evening or at night and can severely affect sleep. Although the condition is relatively common – up to one in 10 older adults suffer from the symptoms, while 2 to 3% are severely affected and seek medical help – little is known about the causes. People with restless legs syndrome often also suffer from other conditions such as depression or anxiety, cardiovascular disease, high blood pressure and diabetes, but the reasons for this are not known.

Previous studies have identified 22 genetic risk loci, i.e. regions in our genome that have changes associated with an increased risk of developing the disease. However, there are still no known “biomarkers” – such as genetic signatures – that could be used to objectively diagnose the disease. To further investigate the disease, an international team led by researchers from the Helmholtz Institute Munich for Neurogenomics, the Institute of Human Genetics at the Technical University of Munich (TUM) and the University of Cambridge has pooled and analyzed data from three genome-wide association studies. In these studies, the DNA of patients and healthy controls was compared to look for differences that occur more frequently in people with restless leg syndrome. By combining the data, the team was able to create a meaningful dataset of more than 100,000 patients and over 1.5 million unaffected controls. The results of the study are published today in Nature Genetics.

Researchers Have Succeeded in Predicting the Risk of this Syndrome

This study is the largest of its kind on this common but poorly understood condition. By understanding the genetic basis of restless legs syndrome, they can hopefully find better ways to treat it and improve the lives of millions of sufferers worldwide. The team identified over 140 new genetic risk loci, increasing the number of known ones eightfold to 164, including three on the X chromosome. The researchers found no major genetic differences between men and women, although the disease is twice as common in women as in men – suggesting that a complex interplay of genetics and environment (including hormones) may explain the sex differences we see 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. These could potentially be targeted by existing drugs, e.g. anticonvulsants such as perampanel and lamotrigine, or used to develop new drugs. Initial 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 such as age, gender and genetic markers to accurately determine who is more likely to suffer from 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 investigate cause-and-effect relationships. This showed 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 it can lead to a decrease in the neurotransmitter dopamine – the researchers found no strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor. According to Professor Juliane Winkelmann from TUM, one of the lead authors of the study, this is the first time that it has been possible to predict the risk of restless leg syndrome. It has been a long road, but now the researchers are able not only to treat but even prevent the occurrence of this disease in patients.