Restless Legs Syndrome-associated intronic common variant in <i>Meis1</i> alters enhancer function in the developing telencephalon

Spieler, Derek; Kaffe, Maria; Knauf, Franziska; Bessa, José; Tena, Juan J.; Giesert, Florian; Schormair, Barbara; Tilch, Erik; Lee, Hyun O.; Horsch, Marion; Czamara, Darina; Karbalai, Nazanin; Toerne, Christine von; Waldenberger, Mélanie; Gieger, Christian; Lichtner, Peter; Claussnitzer, Melina; Naumann, Ronald; Müller‐Myhsok, Bertram; Torres, Miguel; Garrett, Lillian; Rozman, Jan; Klingenspor, Martin; Gailus‐Durner, Valérie; Fuchs, Helmut; Angelis, Martin Hrabě de; Beckers, Johannes; Hölter, Sabine M.; Meitinger, Thomas; Hauck, Stefanie M.; Laumen, Helmut; Wurst, Wolfgang; Casares, Fernando; Gómez-Skármeta, José Luis; Winkelmann, Juliane

doi:10.1101/gr.166751.113

Cited by 101 publications

(110 citation statements)

References 44 publications

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“…Genotyping for 13 of these SNPs was performed on the MassARRAY system using MALDI-TOF mass spectrometry with the iPLEX Gold chemistry (Sequenom Inc, San Diego, CA, USA), as reported by Winkelmann et al (15). The fourteenth SNP, rs11693221(T) is a MEIS1 polymorphism recently shown to be more strongly associated with RLS than previously reported rs6710341(G) or rs2300478(G) (26). Genotypes from this SNP were derived from imputing Genome Wide Data from the cohort using Affymetrix 6.0 arrays.…”

Section: Rls-associated Polymorphismsmentioning

confidence: 99%

Association of low ferritin with PLM in the Wisconsin Sleep Cohort

Moore

Lin

et al. 2015

Sleep Medicine

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Section: Rls-associated Polymorphismsmentioning

confidence: 99%

Association of low ferritin with PLM in the Wisconsin Sleep Cohort

Moore

Lin

et al. 2015

Sleep Medicine

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“…It has therefore been proposed that many underlying causal variants are cis regulatory 1,3 , and multiple anecdotal examples support this hypothesis [4][5][6][7][8] . However, it has been exceedingly difficult to identify causal regulatory variants on a large scale because (i) most GWAS SNPs are not causal but merely in LD with the causal SNP 9,10 and (ii) little is known about the cis-regulatory functions of candidate SNPs.…”

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confidence: 96%

Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms

et al. 2015

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Most disease associations detected by genome-wide association studies (GWAS) lie outside coding genes, but very few have been mapped to causal regulatory variants. Here, we present a method for detecting regulatory quantitative trait loci (QTLs) that does not require genotyping or whole-genome sequencing. The method combines deep, long-read chromatin immunoprecipitation-sequencing (ChIP-seq) with a statistical test that simultaneously scores peak height correlation and allelic imbalance: the genotype-independent signal correlation and imbalance (G-SCI) test. We performed histone acetylation ChIP-seq on 57 human lymphoblastoid cell lines and used the resulting reads to call 500,066 single-nucleotide polymorphisms de novo within regulatory elements. The G-SCI test annotated 8,764 of these as histone acetylation QTLs (haQTLs)—an order of magnitude larger than the set of candidates detected by expression QTL analysis. Lymphoblastoid haQTLs were highly predictive of autoimmune disease mechanisms. Thus, our method facilitates large-scale regulatory variant detection in any moderately sized cohort for which functional profiling data can be generated, thereby simplifying identification of causal variants within GWAS loci.

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“…4,22 Ondo et al 4 suggested that PD could be a risk factor for RLS when secondary factors, such as iron deficiency, are also present. Whereas further experimental studies 23 support the hypothesis of an early basal ganglia development disorder, in PD patients, at least, clinical manifestation does not seem to be triggered by low brain iron storage.…”

Section: Discussionmentioning

confidence: 78%

Serum Ferritin Levels in Parkinson's Disease Patients with and without Restless Legs Syndrome

Muntean

Sixel‐Döring

Trenkwalder

2015

Movement Disord Clin Pract

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Background: The frequency of RLS in Parkinson's disease (PD) patients has been reported to be between 10% and 26%. Several hypotheses have sought to link these two diseases; however, the pathophysiology of RLS in PD patients has yet to be completely defined. Many patients with idiopathic RLS have low serum ferritin levels, which negatively influence RLS symptomatology. Our objective was to investigate the role of iron deficiency in PD patients with and without RLS. Methods: We consecutively included 42 PD inpatients undergoing pharmacological treatment. Patients with anemia, renal insufficiency, or polyneuropathy were excluded from the study. The control group consisted of 42 PD inpatients without RLS (PD-nonRLS), matched for age and severity of PD. RLS was diagnosed clinically according to diagnostic criteria. Serum ferritin levels were measured at admission for all patients. Results: Mean serum ferritin values were 142.20 AE 91.17 ng/dL for PD patients with RLS (PD+RLS) and 160.65 AE 142.57 ng/dL in PD-nonRLS (P = 0.704). There was no difference concerning the total dopaminergic dose (levodopa equivalent dose) between PD+RLS and PD-nonRLS patients (828.22 AE 389.02 vs. 775.32 AE 324.69 mg; P = 0.501). The frequency of dopamine agonist (DA) use did not differ between the two groups (P = 0.306). Conclusions: There were no significant differences in serum ferritin levels between PD+RLS and PD-nonRLS in our study. This suggests a different pathophysiology of RLS in PD patients, where iron deficiency is not necessarily observed. DA use was not found to be associated with the occurrence of RLS symptoms.The relationship between RLS and Parkinson's disease (PD) is controversial. Some studies have shown a higher prevalence of RLS in PD patients, compared to controls, whereas others have failed to demonstrate a significant difference. 1 Although the essential diagnostic criteria for RLS 2 have not yet been validated in PD patients, approximately 10% to 26% of PD patients suffer from RLS-like symptoms, 3-5 often years after manifestation of PD motor symptoms. 4 Other PD patients may develop RLS after successful DBS, when dopaminergic treatment is reduced. 6 A link between RLS and PD has been suggested. Both conditions respond well to dopaminergic treatment and are aggravated by dopaminergic antagonists. 7 They are both associated with periodic limb movements in sleep, which are improved with dopaminergic treatment, especially dopamine agonists. 8,9 However, whereas PD patients with (PD+RLS) and without RLS (PD-nonRLS) show increased echogenicity of the SNc on midbrain sonography (supporting the hypothesis of increased iron concentration), patients with idiopathic RLS are often identified with hypoechogenicity (supporting the hypothesis of decreased iron concentration). This suggests a different underlying pathogenesis, 10,11 probably related to iron storage and transport as well as to brain iron concentrations. Iron and ferritin levels in the cerebrospinal fluid have been found to be reduced in patients with iR...

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Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon

Cited by 101 publications

References 44 publications

Association of low ferritin with PLM in the Wisconsin Sleep Cohort

Association of low ferritin with PLM in the Wisconsin Sleep Cohort

Sensitive detection of chromatin-altering polymorphisms reveals autoimmune disease mechanisms

Serum Ferritin Levels in Parkinson's Disease Patients with and without Restless Legs Syndrome

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