Genetics study points to potential treatments for restless leg syndrome

Scientists have uncovered genetic clues to the cause of restless leg syndrome, a condition that affects up to one in 10 older adults and can severely impair sleep. The discovery, published in Nature Genetics, could help identify individuals at greatest risk of the condition and point to potential ways to treat it. Despite being relatively common, with 2-3% of those affected seeking medical help, little is known about the causes of restless leg syndrome.

An international team led by researchers at the Helmholtz Munich Institute of Neurogenomics, Institute of Human Genetics of the Technical University of Munich (TUM), and the University of Cambridge pooled and analyzed data from three genome-wide association studies. By comparing the DNA of patients and healthy controls, the team created a powerful dataset with more than 100,000 patients and over 1.5 million unaffected controls.

Identifying New Genetic Risk Loci

The study 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, suggesting that a complex interaction of genetics and the environment (including hormones) may explain the observed gender differences.

Two of the genetic differences identified 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, 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 leg syndrome.

Predicting Risk and Exploring Health Implications

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 leg syndrome in nine cases out of ten. Using a technique called Mendelian randomization, which uses genetic information to examine cause-and-effect relationships, the researchers found that restless leg syndrome increases the risk of developing diabetes.

Although low levels of iron in the blood are thought to trigger restless leg syndrome by leading 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.

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 restless leg 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.”

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

As scientists continue to unravel the genetic underpinnings of restless leg syndrome, the findings of this study offer hope for more accurate diagnosis and targeted treatments. By identifying individuals at higher risk and exploring potential drug targets, researchers are paving the way for a better understanding and management of this debilitating condition.
Schormair et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology, and risk prediction. Nature Genetics; 5 June 2024; DOI: 10.1038/s41588-024-01763-1


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