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Am J Hum Genet. 2014 Jul 3;95(1):85-95. doi: 10.1016/j.ajhg.2014.06.005.

Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome.

Author information

1
Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
2
Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, NC 27710, USA.
3
Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany.
4
Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany.
5
Paracelsus Elena Klinik, 34128 Kassel, Germany; Klinik für Neurochirurgie, Georg August Universität, 37075 Göttingen, Germany.
6
Department of Neurology, Medizinische Universität Innsbruck, 6020 Innsbruck, Austria.
7
Institut für Epidemiologie und Sozialmedizin, Westfälische Wilhelms Universität Münster, 48149 Münster, Germany.
8
Zentrum für Schlafmedizin, Charité Universitätsmedizin, 10117 Berlin, Germany.
9
Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Interdisziplinäres Schmerzzentrum, Albert-Ludwigs Universität Freiburg, 79106 Freiburg, Germany; Diakoniewerk München-Maxvorstadt, 80799 Munich, Germany.
10
Klinik für Neurologie, Philipps Universität Marburg, 35039 Marburg, Germany.
11
Abteilung für Neurologie, Paracelsus Klinikum Osnabrück, 49076 Osnabrück, Germany; Klinische Neurophysiologie, Georg August Universität, 37075 Göttingen, Germany.
12
Department of Neurology, Medizinische Universität Wien, 1090 Vienna, Austria.
13
Institute of Epidemiology II, Helmholtz Zentrum München, 85764 Munich, Germany.
14
Institute of Genetic Epidemiology, Helmholtz Zentrum München, 85764 Munich, Germany.
15
Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
16
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Max-Planck Institut für Psychiatrie München, 80804 Munich, Germany; Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
17
Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; Institut für Humangenetik, Helmholtz Zentrum München, 85764 Munich, Germany; Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Department of Neurology and Neurosciences, Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, CA 94304, USA. Electronic address: winkelmann@stanford.edu.

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.

PMID:
24995868
PMCID:
PMC4085638
DOI:
10.1016/j.ajhg.2014.06.005
[Indexed for MEDLINE]
Free PMC Article
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