Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers

Authors

  • Matthew A. Lalli,

    1. Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California
    2. Program in Biomolecular Science and Engineering, University of California at Santa Barbara, Santa Barbara, California
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  • Gloria Garcia,

    1. Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia
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  • Lucia Madrigal,

    1. Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia
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  • Mauricio Arcos-Burgos,

    1. Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia
    2. ANU College of Medicine, Biology and Environment, John Curtin School of Medical Research, The Australian National University, Translational Genomics Group, Translational Medicine Department, Canberra, ACT, Australia
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  • Mary Luz Arcila,

    1. Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California
    2. University of California at Santa Barbara, Department of Molecular, Cellular, and Developmental Biology, Santa Barbara, California
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  • Kenneth S. Kosik,

    Corresponding author
    1. Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, California
    2. Program in Biomolecular Science and Engineering, University of California at Santa Barbara, Santa Barbara, California
    3. University of California at Santa Barbara, Department of Molecular, Cellular, and Developmental Biology, Santa Barbara, California
    • University of California at Santa Barbara, Neuroscience Research Institute, Santa Barbara, California, USA.
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  • Francisco Lopera

    1. Grupo de Neurociencias de Antioquia, Universidad de Antioquia, Medellín, Colombia
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  • Communicated by Christine Van Broeckhoven

Abstract

Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease. Hum Mutat 33:1630–1634, 2012. © 2012 Wiley Periodicals, Inc.

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