👤 Bertram Müller-Myhsok

Restless legs syndrome (RLS) is a frequent neurological disorder which is presented in idiopathic and secondary form. Idiopathic RLS is associated with common genetic variants in four chromosomal regions. Recently, multiple sclerosis (MS) was identified as a common cause for secondary RLS. The aim of our study was to evaluate the prevalence of RLS among Czech patients with MS and to further analyze the impact of known genetic risk factors for RLS in patients with MS. Each patient underwent a semi-structured interview. A patient was considered to be affected by RLS if all four standard criteria had ever been met in their lifetime. The sample was genotyped using 12 single nucleotide polymorphisms within the four genomic regions, which were selected according to the results of previous genome-wide association studies. A total of 765 subjects with MS were included in the study and the diagnosis of RLS was confirmed in 245 subjects (32.1%, 95%CI 28.7-35.4%). The genetic association study included 642 subjects; 203 MS patients with RLS were compared to 438 MS patients without RLS. No significant association with MEIS 1, BTBD9, and PTPRD gene variants was found despite sufficient statistical power for the first two loci. There was a trend for association with the MAP2K5/SCOR1 gene - the best model for the risk allele was the recessive one (p nominal=0.0029, p corrected for four loci and two models=0.023, odds ratio=1.60). We confirmed that RLS prevalence was high in patients with multiple sclerosis, but this form did not share all genetic risk variants with idiopathic RLS. Show less

Restless legs syndrome (RLS) is a sleep related movement disorder that occurs both in an idiopathic form and in symptomatic varieties. RLS is a frequent and distressing comorbidity in end stage renal disease (ESRD). For idiopathic RLS (iRLS), genetic risk factors have been identified, but their role in RLS in ESRD has not been investigated yet. Therefore, a case-control association study of these variants in ESRD patients was performed. The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent case-control samples from Germany and Greece using multiplex PCR and MALDI-TOF (matrix assisted laser desorption/ionisation time-of-flight) mass spectrometry. Statistical analysis was performed as logistic regression with age and gender as covariates. For the combined analysis a Cochran-Mantel-Haenszel test was applied. The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German sample, and 141 and 393 patients, respectively, in the Greek sample. In the German sample, variants in MEIS1 and BTBD9 were associated with RLS in ESRD (P(nom)≤0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (P(nom)≤0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (P(corrected)=0.0013, OR 1.47). This is the first demonstration of a genetic influence on RLS in ESRD patients with BTBD9 being significantly associated. The extent of the genetic predisposition could vary between different subgroups of RLS in ESRD. Show less

Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering. Show less

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. Show less