C9ORF72 Intermediate Repeat Copies Are a Significant Risk Factor for Parkinson Disease

Authors

  • Karen Nuytemans,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
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    • These authors contributed equally to this manuscript.

  • Güney Bademci,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. Kanuni Training and Research Hospital, Clinical Genetics Lab, Kasustu, Trabzon, Turkey
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    • These authors contributed equally to this manuscript.

  • Martin M. Kohli,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
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  • Gary W. Beecham,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Liyong Wang,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Juan I. Young,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Fatta Nahab,

    1. University of Miami, Miller School of Medicine, Department of Neurology, Clinical Research Building, Miami, FL, USA
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  • Eden R. Martin,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • John R. Gilbert,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Michael Benatar,

    1. University of Miami, Miller School of Medicine, Department of Neurology, Clinical Research Building, Miami, FL, USA
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  • Jonathan L. Haines,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, South Nashville, TN, USA
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  • William K. Scott,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Stephan Züchner,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Margaret A. Pericak-Vance,

    1. University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
    2. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
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  • Jeffery M. Vance

    Corresponding author
    1. University of Miami, Miller School of Medicine, Dr. John T. Macdonald Foundation Department of Human Genetics, Miami, FL, USA
    • University of Miami, Miller School of Medicine, John P. Hussman Institute for Human Genomics, Biomedical Research building, Miami, FL, USA
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Corresponding author: Jeffery M. Vance, University of Miami Miller School of Medicine, 1501 NW 10th Ave, Biomedical Research Building, Suite 616 Miami, FL 33136, USA. Tel: (305) 243.5464; Fax: (305) 243.2704; E-mail: jvance@med.miami.edu

Summary

We set out to determine whether expansions in the C9ORF72 repeat found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) families are associated with Parkinson disease (PD). We determined the repeat size in a total of 889 clinically ascertained patients (including PD and essential tremor plus Parkinsonism (ETP)) and 1144 controls using a repeat-primed PCR assay. We found that large C9ORF72 repeat expansions (>30 repeats) were not contributing to PD risk. However, PD and ETP cases had a significant increase in intermediate (>20 to 30+) repeat copies compared to controls. Overall, 14 cases (13 PD, 1 ETP) and three controls had >20 repeat copies (Fisher's exact test p = 0.002). Further, seven cases and no controls had >23 repeat copies (p = 0.003). Our results suggest that intermediate copy numbers of the C9ORF72 repeat contribute to risk for PD and ETP. This also suggests that PD, ALS and FTD share some pathophysiological mechanisms of disease. Further studies are needed to elucidate the contribution of the C9ORF72 repeat in the overall PD population and to determine whether other common genetic risk factors exist between these neurodegenerative disorders.

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