Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel

Authors

  • Kin Y. Mok FRCP (Edin), PhD,

    1. Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Susanne A. Schneider MD, PhD,

    1. Department of Neurology, University of Kiel, Kiel, Germany
    2. Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Daniah Trabzuni PhD,

    1. Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Maria Stamelou MD, PhD,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Mark Edwards PhD, MRCP,

    1. Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Dalia Kasperaviciute PhD,

    1. Department of Clinical and Experimental Epilepsy, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Stuart Pickering-Brown PhD,

    1. University of Manchester, Institute of Brain, Behaviour and Mental Health, Manchester, United Kingdom
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  • Monty Silverdale MD, PhD,

    1. University of Manchester, Institute of Brain, Behaviour and Mental Health, Manchester, United Kingdom
    2. Greater Manchester Neuroscience Centre, Salford Royal Foundation Trust, Greater Manchester, United Kingdom
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  • John Hardy PhD,

    Corresponding author
    1. Department of Molecular Neuroscience, University College London (UCL) Institute of Neurology, London, United Kingdom
    2. Reta Lila Weston Research Laboratories, University College London (UCL) Institute of Neurology, London, United Kingdom
    • Correspondence to: Dr. John Hardy, Departments of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG, London, UK; j.hardy@ucl.ac.uk

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  • Kailash P. Bhatia MD, FRCP

    1. Sobell Department of Motor Neuroscience and Movement Disorders, University College London (UCL) Institute of Neurology, London, United Kingdom
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  • Funding agencies: Dystonia Medical Research Foundation.

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Dystonia is a common movement disorder. A number of monogenic causes have been identified. However, the majority of dystonia cases are not explained by single gene defects. Cervical dystonia is one of the commonest forms without genetic causes identified. This pilot study aimed to identify large effect-size risk loci in cervical dystonia. A genomewide association study (GWAS) was performed. British resident cervical dystonia patients of European descent were genotyped using the Illumina-610-Quad. Comparison was made with controls of European descent from the Wellcome Trust Case Control Consortium using logistic regression algorithm from PLINK. SNPs not genotyped by the array were imputed with 1000 Genomes Project data using the MaCH algorithm and minimac. Postimputation analysis was done with the mach2dat algorithm using a logistic regression model. After quality control measures, 212 cases were compared with 5173 controls. No single SNP passed the genomewide significant level of 5 × 10−8 in the analysis of genotyped SNP in PLINK. Postimputation, there were 5 clusters of SNPs that had P value <5 × 10−6, and the best cluster of SNPs was found near exon 1 of NALCN, (sodium leak channel) with P = 9.76 × 10−7. Several potential regions were found in the GWAS and imputation analysis. The lowest P value was found in NALCN. Dysfunction of this ion channel is a plausible cause for dystonia. Further replication in another cohort is needed to confirm this finding. We make this data publicly available to encourage further analyses of this disorder. © 2013 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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