ArticleAmerican journal of human genetics2014
Targeted resequencing and systematic in vivo functional testing identifies rare variants in MEIS1 as significant contributors to restless legs syndrome.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 4 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
28 citing papers in PubMed, 4 syntheses or guidelines pooled it, 65 citations in OpenAlex.
- Putative Animal Models of Restless Legs Syndrome: A Systematic Review and Evaluation of Their Face and Construct Validity.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Pooled it
- Polysomnographic nighttime features of Restless Legs Syndrome: A systematic review and meta-analysis.Frontiers in neurology · 2022Pooled it
- [Frequent neurological diseases associated with the restless legs syndrome].Der Nervenarzt · 2018Pooled it
- Restless legs syndrome associated with major diseases: A systematic review and new concept.Neurology · 2016Pooled it
- Polygenic risk scores in neurological disorders: restless legs syndrome as a translational model.Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2026Article
- Unraveling Restless Legs Syndrome: A Comprehensive Review of Current Research and Future Directions.International journal of general medicine · 2025Review
- Association between inflammatory cytokines and disease severity in restless legs syndrome.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- A patient-enriched MEIS1 coding variant causes a restless legs syndrome-like phenotype in mice.Sleep · 2024Article
- Genomic analysis identifies risk factors in restless legs syndrome.medRxiv : the preprint server for health sciences · 2023Article
- Genome-wide analysis identified novel susceptible genes of restless legs syndrome in migraineurs.The journal of headache and pain · 2022Article
- Association between thyroid function and disease severity in restless legs syndrome.Frontiers in neurology · 2022Article
- Review
- Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.Nature genetics · 2017Article
- Article
- MEIS1 variant as a determinant of autonomic imbalance in Restless Legs Syndrome.Scientific reports · 2017Article
- Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome.American journal of human genetics · 2017Article
- Animal models of RLS phenotypes.Sleep medicine · 2017Review
- Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration.Investigative ophthalmology & visual science · 2017Article
- Pleiotropic genetic effects influencing sleep and neurological disorders.The Lancet. Neurology · 2017Review
- Genome-wide association analyses of sleep disturbance traits identify new loci and highlight shared genetics with neuropsychiatric and metabolic traits.Nature genetics · 2017Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors at 13 institutions in 4 countries.
Funding
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.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.