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Juliane Winkelmann - One of the best experts on this subject based on the ideXlab platform.
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ORIGINAL ARTICLE MEIS1 and BTBD9: genetic association with restless
2015Co-Authors: Georgios M Hadjigeorgiou, Konrad Oexle, Juliane WinkelmannAbstract:Background 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 caseecontrol association study of these variants in ESRD patients was performed. Methods The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent caseecontrol 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 CochraneManteleHaenszel test was applied. Results 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 (Pnom#0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom#0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected0.0013, OR 1.47). Conclusions 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
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Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.
Sleep, 2014Co-Authors: Hyatt Moore, Juliane Winkelmann, Ling Lin, Laurel Finn, Paul E. Peppard, Emmanuel MignotAbstract:To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P = 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI> 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.
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periodic leg movements during sleep are associated with polymorphisms in BTBD9 tox3 bc034767 meis1 map2k5 skor1 and ptprd
Sleep, 2014Co-Authors: Hyatt Moore, Juliane Winkelmann, Ling Lin, Laurel Finn, Paul E. Peppard, Emmanuel MignotAbstract:To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P = 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI> 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.
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Recent advances in the diagnosis, genetics and treatment of restless legs syndrome
Journal of Neurology, 2009Co-Authors: Claudia Trenkwalder, Birgitte Högl, Juliane WinkelmannAbstract:Knowledge of restless legs syndrome (RLS) has greatly increased in recent years due to the many advances that have been made in diagnosis, management and genetics. Tools have been developed that facilitate the diagnosis and treatment of RLS, in particular the essential diagnostic criteria for RLS have been refined, severity scales (IRLS, RLS-6, JHSS) have been developed, as have instruments that improve diagnostic accuracy and assess for specific aspects of RLS such as augmentation. These newly developed tools have been used in recent population-based studies, which have provided a greater understanding of the epidemiology of RLS, and also within patient-based trials. As far as the genetics of RLS is concerned, linkage studies in RLS families have revealed eight loci but no causally related sequence variant has yet been identified using this approach. Recent genome-wide association studies have identified variants within intronic or intergenic regions of MEIS1, BTBD9, and MAP2K5/LBXCOR1, and PTPRD, raising new pathological hypotheses for RLS. An overview on therapeutic options and recent trials is given based on evidence-based management strategies for this common disorder.
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Genetics of the Restless Legs Syndrome
Aktuelle Neurologie, 2009Co-Authors: Juliane WinkelmannAbstract:In genome-wide association studies genetic risk variations for the restless legs syndrome (RLS) have been identified in the genes MEIS1, BTBD9, PTPRD and LBXCOR1 / MAP2K5 genes. Carriers of one risk allele have an increased risk to suffer from RLS. Further genetic and / or non-genetic or environmental factors must additionally be present for a person to be afflicted by RLS. It is, however, not known which specific factors are involved in this process. The identified genes are involved in the development of the central nervous system. Further research is needed to show whether RLS has components of a neurological development disorder or whether the RLS genes in the adult CNS have completely different functions in relation to RLS and in the adult CNS.
Emmanuel Mignot - One of the best experts on this subject based on the ideXlab platform.
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Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD.
Sleep, 2014Co-Authors: Hyatt Moore, Juliane Winkelmann, Ling Lin, Laurel Finn, Paul E. Peppard, Emmanuel MignotAbstract:To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P = 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI> 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.
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periodic leg movements during sleep are associated with polymorphisms in BTBD9 tox3 bc034767 meis1 map2k5 skor1 and ptprd
Sleep, 2014Co-Authors: Hyatt Moore, Juliane Winkelmann, Ling Lin, Laurel Finn, Paul E. Peppard, Emmanuel MignotAbstract:To examine association between periodic leg movements (PLM) and 13 single nucleotide polymorphisms (SNPs) in 6 loci known to increase risk of restless legs syndrome (RLS).Stanford Center for Sleep Sciences and Medicine and Clinical Research Unit of University of Wisconsin Institute for Clinical and Translational Research.Adult participants (n = 1,090, mean age = 59.7 years) from the Wisconsin Sleep Cohort (2,394 observations, 2000-2012).A previously validated automatic detector was used to measure PLMI. Thirteen SNPs within BTBD9, TOX3/BC034767, MEIS1 (2 unlinked loci), MAP2K5/SKOR1, and PTPRD were tested. Analyses were performed using a linear model and by PLM category using a 15 PLM/h cutoff. Statistical significance for loci was Bonferroni corrected for 6 loci (P = 15 was 33%. Subjects with PLMs were older, more likely to be male, and had more frequent RLS symptoms, a shorter total sleep time, and higher wake after sleep onset. Strong associations were found at all loci except one. Highest associations for PLMI> 15/h were obtained using a multivariate model including age, sex, sleep disturbances, and the best SNPs for each loci, yielding the following odds ratios (OR) and P values: BTBD9 rs3923809(A) OR = 1.65, P = 1.5×10(-8); TOX3/BC034767 rs3104788(T) OR = 1.35, P = 9.0 × 10(-5); MEIS1 rs12469063(G) OR = 1.38, P = 2.0 × 10(-4); MAP2K5/SKOR1 rs6494696(G) OR = 1.24, P = 1.3×10(-2); and PTPRD(A) rs1975197 OR = 1.31, P = 6.3×10(-3). Linear regression models also revealed significant PLM effects for BTBD9, TOX3/BC034767, and MEIS1. Co-varying for RLS symptoms only modestly reduced the genetic associations.Single nucleotide polymorphisms demonstrated to increase risk of RLS are strongly linked to increased PLM as well, although some loci may have more effects on one versus the other phenotype.
Mark P. Deandrade - One of the best experts on this subject based on the ideXlab platform.
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the role of BTBD9 in the cerebellum sleep like behaviors and the restless legs syndrome
Neuroscience, 2020Co-Authors: Shangru Lyu, Mark P. Deandrade, Fumiaki Yokoi, Hong Xing, Pablo D Perez, Marcelo Febo, Arthur S WaltersAbstract:Recent genome-wide association studies (GWAS) have found cerebellum as a top hit for sleep regulation. Restless legs syndrome (RLS) is a sleep-related sensorimotor disorder characterized by uncomfortable sensations in the extremities, generally at night, which are often relieved by movements. Clinical studies have found that RLS patients have structural and functional abnormalities in the cerebellum. However, whether and how cerebellar pathology contributes to sleep regulation and RLS is not known. GWAS identified polymorphisms in BTBD9 conferring a higher risk of sleep disruption and RLS. Knockout of the BTBD9 homolog in mice (BTBD9) and fly results in motor restlessness and sleep disruption. We performed manganese-enhanced magnetic resonance imaging on the BTBD9 knockout mice and found decreased neural activities in the cerebellum, especially in lobules VIII, X, and the deep cerebellar nuclei. Electrophysiological recording of Purkinje cells (PCs) from BTBD9 knockout mice revealed an increased number of non-tonic PCs. Tonic PCs showed increased spontaneous activity and intrinsic excitability. To further investigate the cerebellar contribution to RLS and sleep-like behaviors, we generated PC-specific BTBD9 knockout mice (BTBD9 pKO) and performed behavioral studies. BTBD9 pKO mice showed significant motor restlessness during the rest phase but not in the active phase. BTBD9 pKO mice also had an increased probability of waking at rest. Unlike the BTBD9 knockout mice, there was no increased thermal sensation in the BTBD9 pKO. Our results indicate that the BTBD9 knockout influences the PC activity; dysfunction in the cerebellum may contribute to the motor restlessness found in the BTBD9 knockout mice.
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BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome
Brain Structure and Function, 2020Co-Authors: Shangru Lyu, Mark P. Deandrade, Atbin Doroodchi, Fumiaki Yokoi, Hong Xing, Yi Sheng, Youfeng Yang, Tracy L. Johnson, Stefan Clemens, Michael A. MillerAbstract:Restless legs syndrome (RLS) is characterized by an urge to move legs, usually accompanied by uncomfortable sensations. RLS symptoms generally happen at night and can be relieved by movements. Genetic studies have linked polymorphisms in BTBD9 to a higher risk of RLS. Knockout of BTBD9 homolog in mice ( BTBD9 ) and fly results in RLS-like phenotypes. A dysfunctional dopaminergic system is associated with RLS. However, the function of BTBD9 in the dopaminergic system and RLS is not clear. Here, we made use of the simple Caenorhabditis elegans nervous system. Loss of hpo-9, the worm homolog of BTBD9 , resulted in hyperactive egg-laying behavior. Analysis of genetic interactions between hpo-9 and genes for dopamine receptors ( dop-1, dop-3 ) indicated that hpo-9 and dop-1 worked similarly. Reporter assays of dop-1 and dop-3 revealed that hpo-9 knockout led to a significant increase of DOP-3 expression. This appears to be evolutionarily conserved in mice with an increased D_2 receptor (D_2R) mRNA in the striatum of the BTBD9 knockout mice. Furthermore, the striatal D_2R protein was significantly decreased and Dynamin I was increased. Overall, activities of DA neurons in the substantia nigra were not altered, but the peripheral D_1R pathway was potentiated in the BTBD9 knockout mice. Finally, we generated and characterized the dopamine neuron-specific BTBD9 knockout mice and detected an active-phase sleepiness, suggesting that dopamine neuron-specific loss of BTBD9 is sufficient to disturb the sleep. Our results suggest that increased activities in the D_1R pathway, decreased activities in the D_2R pathway, or both may contribute to RLS.
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the role of BTBD9 in the cerebral cortex and the pathogenesis of restless legs syndrome
Experimental Neurology, 2020Co-Authors: Shangru Lyu, Mark P. Deandrade, Fumiaki Yokoi, Hong Xing, Pablo D Perez, Keer Zhang, Yuning Liu, Marcelo FeboAbstract:Restless legs syndrome (RLS) is a nocturnal neurological disorder affecting up to 10% of the population. It is characterized by an urge to move and uncomfortable sensations in the legs which can be relieved by movements. Mutations in BTBD9 may confer a higher risk of RLS. We developed BTBD9 knockout mice as an animal model. Functional alterations in the cerebral cortex, especially the sensorimotor cortex, have been found in RLS patients in several imaging studies. However, the role of cerebral cortex in the pathogenesis of RLS remains unclear. To explore this, we used in vivo manganese-enhanced MRI and found that the BTBD9 knockout mice had significantly increased neural activities in the primary somatosensory cortex (S1) and the rostral piriform cortex. Morphometry study revealed a decreased thickness in a part of S1 representing the hindlimb (S1HL) and M1. The electrophysiological recording showed BTBD9 knockout mice had enhanced short-term plasticity at the corticostriatal terminals to D1 medium spiny neurons (MSNs). Furthermore, we specifically knocked out BTBD9 in the cerebral cortex of mice (BTBD9 cKO). The BTBD9 cKO mice showed a rest-phase specific motor restlessness, decreased thermal sensation, and a thinner S1HL and M1. Both BTBD9 knockout and BTBD9 cKO exhibited motor deficits. Our results indicate that systematic BTBD9 deficiency leads to both functional and morphometrical changes of the cerebral cortex, and an alteration in the corticostriatal pathway to D1 MSNs. Loss of BTBD9 only in the cerebral cortex is sufficient to cause similar phenotypes as observed in the BTBD9 complete knockout mice.
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the role of BTBD9 in striatum and restless legs syndrome
eNeuro, 2019Co-Authors: Shangru Lyu, Mark P. Deandrade, Fumiaki Yokoi, Hong Xing, Pablo D Perez, Marcelo Febo, Yuning Liu, Arthur S WaltersAbstract:Abstract Restless legs syndrome (RLS) is a sensory-motor neurological disorder characterized by uncomfortable sensations in the extremities, generally at night, which is often relieved by movements. Genome-wide association studies (GWAS) have identified mutations in BTBD9 conferring a higher risk of RLS. Knockout of the BTBD9 homolog in mice (BTBD9) and fly results in motor restlessness and sleep disruption. Clinical studies have found RLS patients have structural and functional abnormalities in the striatum; however, whether and how striatal pathology contributes to the pathogenesis of RLS is not known. Here, we used fMRI to map regions of altered synaptic activity in basal ganglia of systematic BTBD9 knock-out (KO) mice. We further dissected striatal circuits using patch-clamp electrophysiological recordings in brain slices. Two different mouse models were generated to test the effect of specific knockout of BTBD9 in either striatal medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) using the electrophysiological recording, motor and sensory behavioral tests. We found that BTBD9 KO mice showed enhanced neural activity in the striatum, increased postsynaptic currents in the MSNs, and decreased excitability of the striatal ChIs. Knocking out BTBD9 specifically in the striatal MSNs, but not the ChIs, led to rest-phase specific motor restlessness, sleep disturbance, and increased thermal sensation in mice, which are consistent with results obtained from the BTBD9 KO mice. Our data establish the role of BTBD9 in regulating the activity of striatal neurons. Increased activity of the striatal MSNs, possibly through modulation by the striatal ChIs, contributes to the pathogenesis of RLS.
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chapter 80 BTBD9 knockout mice as a model of restless legs syndrome
Movement Disorders (Second Edition)#R##N#Genetics and Models, 2015Co-Authors: Mark P. DeandradeAbstract:Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common neurological disorder with motor, sensory, and circadian components. It is characterized by an uncontrollable urge to move the legs for relief and is generally accompanied by an unpleasant sensation in the legs, with an increase in symptoms during rest or at night. Recent genomewide association studies have linked polymorphisms in BTBD9 with RLS. The function of BTBD9 is mostly unknown. We generated a line of BTBD9 knockout (KO) mice and observed that they had hyperactivity, hypersensitivity to warm stimuli, disruptions in sleep homeostasis, alterations in the iron metabolism and dopamine system, and changes in presynaptic and postsynaptic plasticity and neurotransmission compared to wild-type mice. This therefore suggests that the BTBD9 KO mice are an excellent mouse model of RLS. Furthermore, the battery of tests we conducted provides a basis for future examination of rodent models of RLS.
Andreas Vainas - One of the best experts on this subject based on the ideXlab platform.
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meis1 and BTBD9 genetic association with restless leg syndrome in end stage renal disease
Journal of Medical Genetics, 2011Co-Authors: Barbara Schormair, Peter Lichtner, Jens Plag, Maria Kaffe, Nadine Gross, Darina Czamara, Walter Samtleben, Andreas Ströhle, Ioannis Stefanidis, Andreas VainasAbstract:Background 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 caseecontrol association study of these variants in ESRD patients was performed. Methods The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent caseecontrol 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 CochraneManteleHaenszel test was applied. Results 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 (Pnom#0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom#0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected¼0.0013, OR 1.47). Conclusions 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.
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MEIS1 and BTBD9 - genetic association with RLS in end-stage renal disease
Journal of Medical Genetics, 2011Co-Authors: Barbara Schormair, Peter Lichtner, Jens Plag, Maria Kaffe, Nadine Gross, Darina Czamara, Walter Samtleben, Andreas Ströhle, Ioannis Stefanidis, Andreas VainasAbstract:Background: 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, we performed a case-control association study of these variants in ESRD patients. Methods: We genotyped ten 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 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. Results: The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German 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 (Pnom ≤ 0.004, ORs = 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom ≤ 0.08, ORs = 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected = 0.0013, OR = 1.47). Conclusions: 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.
Barbara Schormair - One of the best experts on this subject based on the ideXlab platform.
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meis1 and BTBD9 genetic association with restless leg syndrome in end stage renal disease
Journal of Medical Genetics, 2011Co-Authors: Barbara Schormair, Peter Lichtner, Jens Plag, Maria Kaffe, Nadine Gross, Darina Czamara, Walter Samtleben, Andreas Ströhle, Ioannis Stefanidis, Andreas VainasAbstract:Background 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 caseecontrol association study of these variants in ESRD patients was performed. Methods The study genotyped 10 iRLS associated variants at four loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, and PTPRD, in two independent caseecontrol 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 CochraneManteleHaenszel test was applied. Results 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 (Pnom#0.004, ORs 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom#0.08, ORs 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected¼0.0013, OR 1.47). Conclusions 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.
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MEIS1 and BTBD9 - genetic association with RLS in end-stage renal disease
Journal of Medical Genetics, 2011Co-Authors: Barbara Schormair, Peter Lichtner, Jens Plag, Maria Kaffe, Nadine Gross, Darina Czamara, Walter Samtleben, Andreas Ströhle, Ioannis Stefanidis, Andreas VainasAbstract:Background: 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, we performed a case-control association study of these variants in ESRD patients. Methods: We genotyped ten 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 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. Results: The study included 200 RLS-positive and 443 RLS-negative ESRD patients in the German 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 (Pnom ≤ 0.004, ORs = 1.52 and 1.55), whereas, in the Greek sample, there was a trend for association to MAP2K5/SKOR1 and BTBD9 (Pnom ≤ 0.08, ORs = 1.41 and 1.33). In the combined analysis including all samples, BTBD9 was associated after correction for multiple testing (Pcorrected = 0.0013, OR = 1.47). Conclusions: 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.
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Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions
Nature Genetics, 2007Co-Authors: Juliane Winkelmann, Barbara Schormair, Peter Lichtner, Stephan Ripke, Lan Xiong, Shapour Jalilzadeh, Stephany Fulda, Benno Pütz, Gertrud Eckstein, Stephanie HaukAbstract: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.
