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Genomic convergence to identify candidate genes for Parkinson disease: SAGE analysis of the substantia nigra

Authors

  • Maher A. Noureddine PhD,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Yi-Ju Li PhD,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Joelle M. van der Walt PhD,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Robert Walters BA,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Rita M. Jewett RN,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Hong Xu MS,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
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  • Tianyuan Wang MS,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Jeffrey W. Walter PhD,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Burton L. Scott MD,

    1. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
    2. Department of Medicine, Duke University, Durham, North Carolina, USA
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  • Christine Hulette MD,

    1. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
    2. Department of Pathology, Duke University, Durham, North Carolina, USA
    3. Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, North Carolina, USA
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  • Don Schmechel MD,

    1. Department of Medicine, Duke University, Durham, North Carolina, USA
    2. Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University, Durham, North Carolina, USA
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  • Judith E. Stenger PhD,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
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  • Fred Dietrich PhD,

    1. Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA
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  • Jeffery M. Vance MD, PhD,

    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
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  • Michael A. Hauser PhD

    Corresponding author
    1. Center for Human Genetics, Duke University, Durham, North Carolina, USA
    2. Duke Udall Center of Excellence, Duke University, Durham, North Carolina, USA
    • Center for Human Genetics, Duke University Medical Center, DUMC, Box 2903, Durham, NC 27710-2903
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Abstract

Genomic convergence is a multistep approach that combines gene expression with genomic linkage to identify and prioritize susceptibility genes for complex disease. As a first step, we previously performed linkage analysis on 174 multiplex Parkinson's disease (PD) families, identifying five peaks for PD risk and two for genes affecting age at onset (AAO) in PD [Hauser et al., Hum Mol Genet 2003;12:671–677]. We report here the next step: serial analysis of gene expression [SAGE; Scott et al., JAMA 2001;286:2239–2242] to analyze substantia nigra tissue from three PD patients and two age-matched controls. We find 933 differentially expressed genes (P < 0.05) between PD and controls, but of these, only 50 genes represented by unique SAGE tags map within our previously described PD linkage regions. Furthermore, genes encoded by mitochondrial DNA are expressed 1.5-fold higher in PD patients versus controls, without an increase in the corresponding nuclear-encoded mitochondrial components, suggesting an increase in mtDNA genomes in PD or a disjunction with nuclear expression. The next step in the genomic convergence process will be to screen these 50 high-quality candidate genes for association with PD risk susceptibility and genetic effects on AAO. © 2005 Movement Disorder Society

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