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Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions

Institute of Human Genetics, GSF National Research Center of Environment and Health, D-85764 Neuherberg, Munich, Germany.
Nature Genetics (Impact Factor: 29.65). 09/2007; 39(8):1000-6. DOI: 10.1038/ng2099
Source: PubMed

ABSTRACT 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.

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    • "There is no definitive diagnostic test for RLS/WED and the pathophysiology is not fully understood. Mechanisms that are thought to play a role include genetic variants (Winkelmann et al., 2007), iron dysregulation (Connor et al., 2011; Dusek et al., 2012), reduced D 2 receptors in the putamen (Connor et al., 2009), and dopamine dysregulation (Trenkwalder and Paulus, 2010). Sensory disturbance (Stiasny-Kolster et al., 2004), altered neurochemistry in the thalamus (Allen et al., 2013; Rizzo et al., 2012), and reduced intracortical inhibition in the hand (Nardone et al., 2006; Tergau et al., 1999) and leg (Tergau et al., 1999) area of motor cortex have also been observed. "
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    ABSTRACT: Objective: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor amplitude but normal dexterity and movement speed and rhythmicity compared to healthy controls. Methods: RLS/WED patients (n=17, 59±7 yrs) with moderate disease and healthy controls (n=17, 58±6 yrs) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. Results: Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. Conclusions: Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. Significance: Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.
    Clinical Neurophysiology 04/2015; 126:736-742.. DOI:10.1016/j.clinph.2014.07.010 · 2.98 Impact Factor
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    • "Three patients with a family history of idiopathic RLS developed olanzapine induced-RLS, indicating that family history may be a risk factor for the condition; however, the underlying mechanisms are not known. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS [16] [17]. Furthermore, one study found that loss of BTBD9 significantly disrupted sleep with concomitant increases in waking and motor activity in a Drosophila model [18]. "
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    ABSTRACT: Only nine patients with olanzapine-induced restless legs syndrome (RLS) have been reported in the literature to our knowledge. We describe two patients with olanzapine-induced RLS treated at our hospital and review the nine reported patients. There were five women and six men aged between 28 and 62years in the overall group. RLS symptoms emerged at olanzapine doses between 2.5 and 20mg. The symptoms improved in all patients when the dose was reduced and immediately disappeared when the medication was stopped. International Restless Legs Scale (IRLS) scores ranged from 10 to 35. Three patients had a family history of idiopathic RLS. Supplemental drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient, while two patients did not respond to the drug. Propoxyphene effectively relieved symptoms in one patient who did not respond to ropinirole or clonazepam. RLS symptoms did not recur following substitution of other antipsychotic drugs for olanzapine. In conclusion, olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. More than half of the patients experienced severe to very severe symptoms. A dose-dependent relationship was observed between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapine-induced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine.
    Journal of Clinical Neuroscience 05/2014; 21(9). DOI:10.1016/j.jocn.2014.01.007 · 1.32 Impact Factor
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    • "We used highresolution melting curve analysis with LightScanner (IDAHO Technology, Inc.). The targeted region was the 32-kb LD block (hg18; chr2: 66,601,989–66,635,212) as defined by the finemapping of the original GWAS signal using tagging-SNPs of the MEIS1 gene and 6 10 kb 59 and 39 of sequence in 903 cases and 891 controls of European ancestry (Winkelmann et al. 2007). Oligonucleotide sequences for 145 amplicons are available in Supplemental Table S7. "
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    ABSTRACT: Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.
    Genome Research 03/2014; DOI:10.1101/gr.166751.113 · 13.85 Impact Factor
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