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Restless Leg Syndrome-Related Genetic Loci Identified in GWAS Meta-Analysis

NEW YORK – New research has expanded on the set of genetic contributors linked to restless leg syndrome (RLS), suggesting that the suite of genetic variants involved in the quality of life-altering chronic sensory-motor condition are similar between biological sexes, despite an overrepresentation of RLS previously reported in women.

"Our results are exciting because they indicate that the genetic underpinnings of RLS are quite similar in both sexes and therefore unlikely to explain the observed difference in prevalence between men and women," co-first and corresponding author Barbara Schormair, a neurogenomics researcher affiliated with Helmholtz Zentrum München and the Technical University of Munich, said in an email. Consequently, she explained, it will likely be "essential to study environmental or nongenetic risk factors and gene-environment interactions here, possibly focusing on the effects of pregnancy on RLS risk."

As they reported in Nature Genetics on Wednesday, Schormair and colleagues from Germany, the UK, and elsewhere brought together data from three previous genome-wide association studies to conduct a meta-analysis aimed at uncovering genetic contributors to RLS using data for 116,647 RLS cases and more than 1.5 million unaffected controls.

Across all of the participants profiled, the team picked up 164 new and known RLS-associated loci, including more than 140 risk loci not reported in the past.

At least two RLS-related loci fell in glutamate receptor genes targeted by existing anticonvulsant drugs, the researchers reported, and nearly a dozen other candidate RLS genes are targeted by approved drugs, highlighting potential treatment strategies that may stem from the genetic data.

Indeed, Schormair noted that she and her colleagues "identified likely candidate genes in all genome-wide significant risk loci and mapped these against the druggable genome to identify potential targets for either developing new drugs or repurposing existing drugs for treatment of RLS."

Although RLS is believed to turn up roughly twice as often in women as men, the investigators' subsequent analyses performed in men and women led to similar genetic associations, suggesting environmental contributors such as hormone or blood iron levels may contribute to the difference in prevalence.

"[T]his is the first time we were able to investigate the genetics of RLS in men and women separately," Schormair explained. "Previous studies had much smaller sample size, so splitting them according to sex would have resulted in quite low study power."

In a series of follow-up analyses, the researchers went on to explore strategies for predicting RLS as well as examine the biological basis of the condition and its relationship to other traits and diseases. With the help of machine learning, for example, the team came up with a strategy for predicting the risk of RLS based on genetic and nongenetic contributors. It also found enrichment for the expression of RLS-related genes in neuron and neuroblast cell types by analyzing tissue-specific expression data in version 8 of GTEx, along with single-cell sequencing data from mouse nervous system samples.

In Mendelian randomization analyses, meanwhile, the researchers narrowed in on apparent causal ties between RLS and type 2 diabetes, Schormair added, hinting that "diagnosing and treating RLS properly could help also with type 2 diabetes."

"Collectively, our study marks a substantial advance in deciphering the genetic basis of RLS and paves the way for improving treatment and prevention strategies," the authors reported, though they cautioned that GWAS so far have focused on individuals of European ancestry and noted that "biobank-scale longitudinal datasets with detailed medical and lifestyle information and high-quality RLS phenotyping are lacking."