Genomewide SNP assay reveals mutations underlying Parkinson disease

Authors

  • Javier Simon-Sanchez,

    1. Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland
    2. Unidad de Genética Molecular, Departamento de Genómica y Proteómica, Instituto de Biomedicina de Valencia-Consejo Superior de Investigaciones Sientificas (CSIC), Valencia, Spain
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    • Javier Simon-Sanchez, Sonja Scholz, Maria del Mar Matarin and Hon-Chung Fung contributed equally to this work.

  • Sonja Scholz,

    1. Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland
    2. Reta Lila Weston Institute and Departments of Molecular Neuroscience and Neurodegenerative Disease, Institute of Neurology, London, United Kingdom
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    • Javier Simon-Sanchez, Sonja Scholz, Maria del Mar Matarin and Hon-Chung Fung contributed equally to this work.

  • Maria del Mar Matarin,

    1. Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland
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    • Javier Simon-Sanchez, Sonja Scholz, Maria del Mar Matarin and Hon-Chung Fung contributed equally to this work.

  • Hon-Chung Fung,

    1. Reta Lila Weston Institute and Departments of Molecular Neuroscience and Neurodegenerative Disease, Institute of Neurology, London, United Kingdom
    2. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
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    • Javier Simon-Sanchez, Sonja Scholz, Maria del Mar Matarin and Hon-Chung Fung contributed equally to this work.

  • Dena Hernandez,

    1. Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland
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  • J Raphael Gibbs,

    1. Reta Lila Weston Institute and Departments of Molecular Neuroscience and Neurodegenerative Disease, Institute of Neurology, London, United Kingdom
    2. Computational Biology Core, National Institutes of Health, Bethesda, Maryland
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  • Angela Britton,

    1. Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland
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  • John Hardy,

    1. Reta Lila Weston Institute and Departments of Molecular Neuroscience and Neurodegenerative Disease, Institute of Neurology, London, United Kingdom
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  • Andrew Singleton

    Corresponding author
    1. Molecular Genetics Unit, National Institutes of Health, Bethesda, Maryland
    • Molecular Genetics Unit, National Institutes of Health, Bethesda, MD 20892
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  • Communicated by Ann-Christine Syvänen

  • This article is a US Government work and, as such, is in the public domain in the United States of America.

Abstract

Technologies that allow genotyping of more than 100,000 polymorphisms in a single assay enable the execution of genomewide SNP (GWSNP) association studies to identify common genetic variants underlying traits. Less appreciated is the ability of GWSNP assays to map and directly identify rare mutations that cause disease. Here we show the use of this approach in identifying rare structural mutations involved in disease using a large cohort of Parkinson disease (PD) patients and neurologically normal controls by examination of genotype data and copy number metrics. This approach revealed a patient with homozygous mutation at the PARK2 locus. In addition, two heterozygous deletion mutations and five heterozygous duplication mutations within PARK2 were identified in PD subjects and controls. All mutations were confirmed by independent gene dosage experiments. These data demonstrate the utility of this approach in the direct detection of mutations that underlie disease. Hum Mutat 29(2), 315–322, 2008. Published 2007 Wiley-Liss, Inc.

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