Restless legs syndrome (RLS) is characterized by restless, painful legs that do not settle down at night. The causes are largely unknown. An international team led by the Technical University of Munich (TUM) and the Helmholtz Center has now carried out the world’s largest genome-wide association study on the genetic causes of the disorder. They discovered 13 new risk-associated genetic variants and identified underlying candidate biological processes.

Juliane Winkelmann, Professor of Neurogenetics at the TUM and Head of the Institute of Neurogenomics at the Helmholtz Center Munich, and her team have been researching this neurological disorder for over a decade. She and her team have already found that genetic factors play a role. With the help of international partners from Cambridge University in the UK and the US company 23andMe, they have now carried out the world’s largest study of its kind on 45,000 patients.

“We were able to identify a total of 19 risk-associated genetic variants, of which 13 are new. We’re confident that our findings will significantly improve our understanding of the molecular causes of restless legs syndrome,” said Dr. Barbara Schormair of the Institute of Neurogenomics at the Helmholtz Center in Munich and one of the first authors of the study. The term “risk-associated variants” denotes point variations in the sequence of letters in the DNA molecule that are more common among individuals with a disorder than among those without it. Genes associated with the development of the disorder are located at, or at least near, such variants.

The international team compared the genetic data of 15,000 patients with those of 95,000 people from the general population. The results were subsequently confirmed in a further study with 31,000 new patient data sets and more than 280,000 control data sets.

The researchers also investigated the biological processes that are most likely associated with the risk-associated variants and made a surprising discovery: they found that genes involved in the embryonic development of the nervous system are mainly involved – despite the fact that the condition usually manifests itself decades later. “This suggests that abberations in certain congenital features of the nervous system only become apparent much later in the form of restless legs syndrome. Armed with a better understanding of the causes, we can start to think about appropriate treatments. Our genetic study has taken us a big step forward in finding new and better treatment options for our patients,” Professor Juliane Winkelmann said, summarizing the findings of the research team, which included Dr. Steven Bell and Dr. Emanuele Di Angelantonio of Cambridge University and Professor Bertram Müller-Myhsok of the Max Planck Institute of Psychiatry.

The drug thalidomide affects a cellular process which, according to the new study, could also play a role in restless legs syndrome. Therefore it could be a potential candidate, the scientists said. But with restrictions: Thalidomide used to be prescribed for the treatment of insomnia during pregnancy but resulted in serious birth defects. The question of whether the drug can be used for the treatment of restless legs syndrome in men or postmenopausal women for whom other forms of treatment are unsuitable can only be answered with the help of carefully designed clinical studies, the scientific team added.