Restless leg syndrome study reveals new risk genes

And how that could lead to new treatments...
07 June 2024

Interview with 

Steven Bell, University of Cambridge

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This month’s news looks into a genetic study into restless leg syndrome, or RLS, which causes those afflicted to have sudden strong urges to move their legs. This long-term neurological condition can have very detrimental effects on the sufferer’s health, but research into its risk factors is not nearly as advanced as other illnesses. But, that’s something a new study just published in Nature Genetics has changed. Co-author on the study is the University of Cambridge’s Steven Bell...

Steven - Restless leg syndrome or RLS as it's often referred to, is a neurological condition that causes a strong, often irresistible urge to move your legs, especially when you're resting or trying to sleep. And people with restless leg syndrome frequently describe it as a tingling, crawling, or creeping sensation inside their legs, similar to insects crawling under their skin. In more severe cases, it can feel like a deep aching, throbbing, or even burning, making it almost impossible to stay still. And it's thought to affect up to 1 in 10 in the European and North American population. And many people with RLS actually suffer in silence as their symptoms are frequently dismissed as fidgeting. So as you can imagine, this is incredibly frustrating and isolating, and the constant need to move one's legs disrupts their sleep, which can lead to chronic fatigue, irritability, and difficulty concentrating during the day. So it's hardly surprising that living with RLS also takes an emotional toll on people causing anxiety and depression due to relentless discomfort and the lack of understanding from others. And it's one of those conditions that also affects people's partners as well as the constant movements and need to get up will disrupt their sleep also.

Will - Had there been any research into this into the past then? Because surely if it's this detrimental, we'd have wanted to know more about it.

Steven - There have been multiple studies in the past, including genetic studies that have shown high concordance in identical twins as well as a positive family history in up to 60% of individuals who have RLS, which suggests a strong genetic component. And it's been about 20 years since the first genome wide association study of RLS was performed. And this identified three areas of the genome associated with RLS. And since then, the number has steadily trickled forward to 22 areas in total at the last count in 2020.

Will - Why did you, and people before you, decide to take a genetic approach to this particular illness?

Steven - That's a great question, and because RLS has so a few treatments available for it, one means of identifying potential avenues and routes to treatment is taking an agnostic approach via genome-wide association studies where we can identify specific areas of the genome associated with risk of RLS and see the proteins involved in this and whether these are tractable to modulate or targeting drug and therefore serve as a new treatment option for people with RLS. One of the other major differentiating factors is that our investigation was the first one to look at the genetic architecture of restless leg syndrome separately for men and women. And this is quite important as RLS affects women more frequently than men, with a reported prevalence increase of 30 to 50 percent in women. But up until now there'd been no systematic comparison of the genetic risk between sexes.

Will - The previous studies kind of tapped out at 20 risk genes, 20 genes that you'd want to look at, in order to find out whether or not you may or may not be at risk of having RLS. Did this study bump that number up?

Steven - Yes, significantly so. So we identified 161 genetic risk loci that were associated with restless leg syndrome and of these 139 were newly discovered, which represents an eightfold increase in the total number of areas of the genome that we now know to be associated with restless leg syndrome.

Will - There's a disparity between male and females. Were any of those new risk areas found on the sex chromosome?

Steven - So there were free associations on the X chromosome that we found to differ in risk of RLS overall. There were six loci that were statistically significantly different across the genome and between sex. However, these were direct concordance. That is, they were always at risk increasing in both men and women. It was just of a different magnitude and there was no consistent direction of higher risk in men always, or women always. But one of the things that were interesting about the analysis of sex were, despite the fact that we've seen a strong genetic correlation in risk of RLS across the genome in men and women, we observed that the heritability, that is the proportion of variation in restless leg syndrome that's attributed to genetic factors, was actually higher in women. So it was 32% compared to 13% for men. This emphasised the importance of studying such phenomena in genetically susceptible individuals and hopefully this will pave the way for further work to better understand precisely what these risk factors are and anything that can be done to reduce the sex disparities in the condition.

Will - Now that you've got new risk areas in the genes that might dictate whether or not you are at risk of getting RLS, what can you then do with that?

Steven - That's the million pound question really isn't it, <laugh>? And unfortunately, as practically in all studies of this kind, the short answer is there's nothing that can be done at least immediately to translate these directly to the clinic. However, a slightly more convoluted answer to that is that whilst work still needs to be done to translate our findings to the clinic, our results could drastically shorten the time taken for new treatments to be available to those suffering from more or less in the future. For example, via repurposing existing drugs to be used in the treatment of restless leg syndrome or helping to prioritise the development of entirely new therapies. Our work actually involved mapping the genes that we identified to be associated with restless leg syndrome with medications that target them. And examples that we found were two glutamate receptors. GRIA4, a target of telampanel, and GRIA1, which is a target of perampanel, both of which are anti-convulsant therapies used in the treatment of epilepsy. And as these drugs have already undergone all of the extensive safety testing and are used in existing clinical practice, the trials that would be needed to test for their efficacy in RLS would be quite drastically shorter and deliver a fraction of the time and cost. And I guess all the other genomic loci that we identified, they still can help in prioritising candidates for drugs development as only about 10% of drug development programs eventually receive approval. And an analysis published in Nature back in April showed that the probability of success for a drug that has genetic support is 2.6 times greater. And crucially, this is most pronounced in phase two and phase three clinical trials. So it's not to say that the path from obtaining a locus identified during a GWAS to a drug target is ever going to be straightforward or easy far from it because extensive studies are needed to identify the causal variance and understand their functional effects. But we've been able to provide a short list of potential candidates to be investigated further and have made our data available as well, so that further computational analysis in this area can be formed by others to support or deprioritise members of this list.

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