SLEEP 2026 | Exploring the genetic architecture of restless legs syndrome

Well, just to give a background on the genetics of RLS, about one-third of it is thought to be familial, and there have been several studies that have looked for actual causal genes in RLS, and they’ve not been able, through linkage, that’s the technique that’s used, to find an actual gene associated with RLS, but they found several chromosomes, several linked chromosomes. But the other way that genetics has been approached in RLS is to do GWAS studies, genome-wide association studies. And these are studies where you look for a gene that occurs more frequently or a single nucleotide polymorphism in RLS. It doesn’t imply causality, but it implies some kind of connection. So what we did was we took it a step further. What we did was to take a look at, because we were looking, our basic project was to look for comorbidities in RLS. And it’s been known that there are many comorbidities that are different diseases that occur more commonly with RLS, such as hypertension and heart disease and stroke and immunological diseases such as multiple sclerosis and rheumatoid arthritis, hypothyroidism. And so what we did was to, there’s a worldwide catalog of all the GWAS studies that were done. And what we did was to take a look at the SNPs, single nucleotide polymorphisms that are more common in RLS, and find out if in that same catalog, those same SNPs were associated with other diseases, such as the ones I mentioned before. And it turned out that they were. So the first study that we did would imply that the overlap of those comorbidities with RLS may have a genetic basis because they actually have the same change in the DNA. And then the second study we did was a PheWAS study. Now, a GWAS study is where you take the trait, for example, the restless leg syndrome, and you try to find out the genes or polymorphisms that we talked about. And as I mentioned, there are about 365 of them. So a PheWAS study is just the opposite. What you do is you take the genes that you’ve discovered and you throw them against a huge population of patients, a random population of patients, so at Vanderbilt we had 72,000 some patients that were already genotyped, and what we did was compare the known SNPs from the GWAS catalog to the SNPs that the patient actually had, and the outcome, the endpoint, was to find out what diseases they had, and it turns out, yes, they had more hypertension. Actually, clinically, so you go from the gene to the trait, as opposed to GWAS, you go from the trait to the gene. And they had more hypertension and multiple sclerosis and immunological disorders. And we actually found perhaps a new locus for multiple sclerosis and some of these immunological disorders that actually had not been found in the GWAS catalog, but the patients did have more of these immunological disorders. A lot more has to be done to prove that it’s an actual locus. But again, the research makes the same point that maybe a part of the reason that these comorbid disorders exist or coexist with RLS may have a genetic basis. And so that’s all I have to say.

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