Genome scan in familial late-onset Alzheimer's disease: A locus on chromosome 6 contributes to age-at-onset

Authors

  • Wei Zhao,

    1. Department of Biostatistics, University of Washington, Seattle, Washington
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  • Elizabeth E. Marchani,

    1. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington
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  • Charles Y.K. Cheung,

    1. Department of Biostatistics, University of Washington, Seattle, Washington
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  • Ellen J. Steinbart,

    1. Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington
    2. Department of Neurology, University of Washington, Seattle, Washington
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  • Gerard D. Schellenberg,

    1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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  • Thomas D. Bird,

    1. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington
    2. Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, Washington
    3. Department of Neurology, University of Washington, Seattle, Washington
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  • Dr. Ellen M. Wijsman

    Corresponding author
    1. Department of Biostatistics, University of Washington, Seattle, Washington
    2. Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington
    3. Department of Genome Sciences, University of Washington, Seattle, Washington
    • Division of Medical Genetics, Department of Medicine, University of Washington, Box 357720, Seattle, WA 98195-7720.
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  • Conflicts of interest: nothing to declare.

  • How to Cite this Article: Zhao W, Marchani EE, Cheung CYK, Steinbart EJ, Schellenberg GD, Bird TD, Wijsman EM. 2013. Genome Scan in Familial Late-Onset Alzheimer's Disease: A Locus on Chromosome 6 Contributes to Age-at-Onset. Am J Med Genet Part B 162B:201–212.

Abstract

Alzheimer's disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early-onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age-at-onset. Here, we present the first genome-scan analysis of the complete, well-characterized University of Washington LOAD sample of 119 pedigrees, using age-at-onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age-at-onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12-14, and 19p13.12. These results provide the first independent confirmation of an AD age-at-onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted. © 2013 Wiley Periodicals, Inc.

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