The findings are a big step in understanding the underlying causes of and potential treatment options for RLS.

There is much left to be discovered about the molecular causes and pathophysiology of restless legs syndrome (RLS), a neurological sleep disorder characterized by the urge to move the legs at night that affects up to 12 million people in the United States alone, and the proper approach to treatment. However, it is known that genetic factors can play a role in susceptibility to RLS. A team of researchers led by the Technical University of Munich (TUM) and the Institute of Neurogenomics at the Helmholtz Center Munich are working to pinpoint RLS risk-associated genetic variants, which are indicative of point variations in the sequence of letters in the DNA molecule that are more common in people with RLS.

In a recent meta-analysis study published in The Lancet Neurology, with assistance from Cambridge University and the genetic testing company 23andMe, the team found 19 of these genetic risk variants, 13 of which had never been identified before. The large study had the participation of 45,000 patients.

Barbara Schormair, MD, one of the lead authors of the study, says there are two goals to this research. “First, we want to understand the molecular mechanisms which cause RLS or influence its onset and severity. Second, we want to use this knowledge about the underlying pathophysiology of RLS to promote the development or improvement of treatment options for RLS patients.”

Schormair says that, generally, the cause of RLS is still unknown, but understanding how genetics play a role can help in the quest for more answers. “We can nominate genes and genetic risk variants for follow-up studies in animal models or in vitro models in cell culture. These studies can shed light on the molecular processes and cell types involved in disease risk and thereby provide new targets for drug development.”

Despite what’s been discovered, there are no direct clinical implications of this study that can be transferred to patients or clinical use immediately, according to Schormair. But she notes that the results suggest processes during early development of the nervous system play a role in RLS susceptibility, even though the disorder does not manifest itself until later on in life. As coauthor Juliane Winkelmann, MD, professor of neurogenetics at the TUM and head of the Institute of Neurogenomics at the Helmholtz Center Munich, said in a release, “This suggests that aberrations 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.”

Schormair adds, “Our study provides new genomic regions associated with the risk to develop the disease. These serve as entry points for follow-up studies for all researchers working on RLS. Finding the genes and genetic risk variants involved in RLS and dissecting their effect and function in individual cells and cell types and their impact on the development of the nervous system will help us in understanding the causes of RLS. This in turn will enable the development of new and improved therapeutic options for treatment, and possibly diagnosis or prevention of the disease.”

The results of this study are a leap forward in finding the causes and, ideally, potential treatments for RLS, and understanding the genetics and biological processes is key to achieving this goal. However, more research needs to be done in order to close the existing gap. “In terms of genetic risk factors, we still haven’t discovered all contributors,” says Schormair. “The 19 risk loci now account for about 60% of the heritability of RLS which is due to common genetic risk factors. Additional genetic factors, including rare genetic variants, that have an impact on RLS susceptibility remain to be found and are required to complete the picture of the genetic architecture of RLS.”

The next step for researchers is to study the known risk loci in-depth to understand the underlying molecular biology and its role in RLS. Schormair says, “Such functional studies are needed to enable developments aimed at better treatment options for individuals suffering from RLS.”

Dillon Stickle is associate editor for Sleep Review.