Genetics of restless legs syndrome
Introduction
For years, researchers have investigated families with restless legs syndrome (RLS) by means of classical linkage analysis, under the assumption that RLS is a Mendelian monogenic disorder. However, the approach to identifying a single disease-causing gene initially failed. Most of these linkage analysis studies resulted in large genomic regions with only borderline significant linkage (LOD) scores. Despite large sequencing efforts for genes located in these regions, no causally-related sequence variant has ever been identified using this approach. It is now obvious that RLS is a classical complex genetic disorder in which common as well as rare genetic variants contribute to the phenotype. Genome-wide association studies (GWAS) have successfully identified common variants and enlargement of the sample sizes, and meta-analyses to identify the entire spectrum of common variants in RLS are still ongoing. Follow-up studies of the GWAS loci and the search of rare variants will address the contribution of rare variants in RLS to better understand the genetic architecture of this disorder.
Section snippets
The search for common variants: GWAS, an update
RLS was among the first disorders to benefit immensely when GWAS became feasible. Even though it was well established that genetic predisposition plays a crucial role in RLS, corresponding risk genes had remained elusive until then. GWAS were motivated by the “common disease–common variant” hypothesis, which posits that many common genetic variants, each with a small to moderate effect, determine the genetic risk of common complex disorders such as RLS [1]. Common variants are variants with a
The search for rare variants: whole exome sequencing and whole genome sequencing studies of RLS
Rare variants, that is, genetic variants with a MAF of <1% in the population, are currently at the center of attention in genetic studies of common complex diseases such as RLS. For years, the focus has been on common variants with a MAF ≥5%, and GWAS have successfully identified many of these risk variants, which, however, have only small to moderate effects. The availability of next-generation sequencing is now changing the game. It allows sequencing of the coding part of the genome (whole
Periodic limb movements in RLS: an endophenotype or a distinct entity?
This question has been brought forward by the observation of an association of the common RLS-associated SNP rs3923809 to PLMs in the absence of RLS sensory symptoms in two cohorts from Iceland and the US [5], [22]. Following up on these reports, the two cohorts were re-phenotyped and partly enlarged and associated SNPs in the six known risk loci for RLS were tested for association (D. Rye, personal communication). First, within the Icelandic cohort (N = 989) recruited from the general
From gene to function
Although RLS is a common disorder, the genetic mechanisms underlying it may be far less than that which is typically observed in other disorders with similar prevalence. To this day, the MEIS1 locus remains one of the strongest genetic associations ever reported in any common disease. It is now possible to test for the existence of links between the RLS genes identified by GWAS and genes that are known to encode proteins involved in iron metabolism. Iron metabolism is an important
Future research
A major part of the heritability of RLS currently remains unexplained. The known risk variants and respective candidate genes are mostly solitary entities that are not connected in molecular networks. To fill these gaps, additional risk variants have to be identified. Larger sets of candidate genes may be able to show a significant enrichment of components of specific molecular pathways. Such analyses will highlight candidate mechanisms for RLS pathophysiology.
So far, RLS genetic studies have
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Restless legs syndrome in internal medicine
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2021, Mayo Clinic ProceedingsRestless Legs Syndrome and Severe Preeclampsia: A Case-Control Study
2020, Journal of Obstetrics and Gynaecology CanadaCitation Excerpt :The pathophysiology of RLS during pregnancy is similar to that of pre-existing RLS, exacerbated by the changes associated with gestation, in particular iron deficiency and dopamine dysfunction and the association between them. The most widely accepted hypothesis is that iron metabolism in the brain can be affected by genetic predisposition,10 leading to abnormal function of dopamine an ultimately to RLS symptoms. The basis of this hypothesis is iron's role as a cofactor of tyrosine hydroxylase, a critical enzyme for the conversion of tyrosine to dopamine.5