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Targeted Resequencing and Systematic In Vivo Functional Testing Identifies Rare Variants in MEIS1 as Significant Contributors to Restless Legs Syndrome

Overview of attention for article published in American Journal of Human Genetics, July 2014
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Title
Targeted Resequencing and Systematic In Vivo Functional Testing Identifies Rare Variants in MEIS1 as Significant Contributors to Restless Legs Syndrome
Published in
American Journal of Human Genetics, July 2014
DOI 10.1016/j.ajhg.2014.06.005
Pubmed ID
Authors

Eva C. Schulte, Maria Kousi, Perciliz L. Tan, Erik Tilch, Franziska Knauf, Peter Lichtner, Claudia Trenkwalder, Birgit Högl, Birgit Frauscher, Klaus Berger, Ingo Fietze, Magdolna Hornyak, Wolfgang H. Oertel, Cornelius G. Bachmann, Alexander Zimprich, Annette Peters, Christian Gieger, Thomas Meitinger, Bertram Müller-Myhsok, Nicholas Katsanis, Juliane Winkelmann

Abstract

Restless legs syndrome (RLS) is a common neurologic condition characterized by nocturnal dysesthesias and an urge to move, affecting the legs. RLS is a complex trait, for which genome-wide association studies (GWASs) have identified common susceptibility alleles of modest (OR 1.2-1.7) risk at six genomic loci. Among these, variants in MEIS1 have emerged as the largest risk factors for RLS, suggesting that perturbations in this transcription factor might be causally related to RLS susceptibility. To establish this causality, direction of effect, and total genetic burden of MEIS1, we interrogated 188 case subjects and 182 control subjects for rare alleles not captured by previous GWASs, followed by genotyping of ∼3,000 case subjects and 3,000 control subjects, and concluded with systematic functionalization of all discovered variants using a previously established in vivo model of neurogenesis. We observed a significant excess of rare MEIS1 variants in individuals with RLS. Subsequent assessment of all nonsynonymous variants by in vivo complementation revealed an excess of loss-of-function alleles in individuals with RLS. Strikingly, these alleles compromised the function of the canonical MEIS1 splice isoform but were irrelevant to an isoform known to utilize an alternative 3' sequence. Our data link MEIS1 loss of function to the etiopathology of RLS, highlight how combined sequencing and systematic functional annotation of rare variation at GWAS loci can detect risk burden, and offer a plausible explanation for the specificity of phenotypic expressivity of loss-of-function alleles at a locus broadly necessary for neurogenesis and neurodevelopment.

Twitter Demographics

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Mendeley readers

The data shown below were compiled from readership statistics for 32 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Austria 2 6%
United States 1 3%
Japan 1 3%
Netherlands 1 3%
Unknown 27 84%

Demographic breakdown

Readers by professional status Count As %
Researcher 14 44%
Student > Ph. D. Student 6 19%
Professor > Associate Professor 4 13%
Professor 2 6%
Student > Master 2 6%
Other 4 13%
Readers by discipline Count As %
Agricultural and Biological Sciences 12 38%
Medicine and Dentistry 10 31%
Biochemistry, Genetics and Molecular Biology 4 13%
Neuroscience 2 6%
Computer Science 1 3%
Other 3 9%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 July 2014.
All research outputs
#9,616,357
of 12,018,607 outputs
Outputs from American Journal of Human Genetics
#4,135
of 4,343 outputs
Outputs of similar age
#129,669
of 192,953 outputs
Outputs of similar age from American Journal of Human Genetics
#27
of 27 outputs
Altmetric has tracked 12,018,607 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
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We're also able to compare this research output to 27 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.