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April 12, 2011; 76 (15) Articles

Olfactory copy number association with age at onset of Alzheimer disease

C.A. Shaw, Y. Li, J. Wiszniewska, S. Chasse, S.N.Y. Zaidi, W. Jin, B. Dawson, K. Wilhelmsen, J.R. Lupski, J.W. Belmont, R.S. Doody, K. Szigeti
First published April 11, 2011, DOI: https://doi.org/10.1212/WNL.0b013e3182166df5
C.A. Shaw
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Y. Li
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J. Wiszniewska
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S. Chasse
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S.N.Y. Zaidi
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W. Jin
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Citation
Olfactory copy number association with age at onset of Alzheimer disease
C.A. Shaw, Y. Li, J. Wiszniewska, S. Chasse, S.N.Y. Zaidi, W. Jin, B. Dawson, K. Wilhelmsen, J.R. Lupski, J.W. Belmont, R.S. Doody, K. Szigeti
Neurology Apr 2011, 76 (15) 1302-1309; DOI: 10.1212/WNL.0b013e3182166df5

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This article has a correction. Please see:

  • Olfactory copy number association with age at onset of Alzheimer disease - May 31, 2011
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Abstract

Objectives: Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD.

Methods: The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV.

Results: The discovery sample identified a chromosomal segment on 14q11.2 (19.3–19.5 Mb, NCBI build 36, UCSC hg18 March 2006) as a region of interest (genome-wide adjusted p = 0.032) for association with AAO of AD. This region encompasses a cluster of olfactory receptors. The replication sample confirmed the association (p = 0.035). The association was found for each APOE4 gene dosage (0, 1, and 2).

Conclusion: High copy number in the olfactory receptor region on 14q11.2 is associated with younger age at onset of AD.

Footnotes

  • Study funding: Supported by Baylor College of Medicine through start-up funds to the PI. The Affymetrix dataset was provided to the PI from the Texas Alzheimer Research Consortium funded by the State of Texas. The funders have no role in the study.

  • Supplemental data at www.neurology.org

  • AAO
    age at onset
    aCGH
    array comparative genome hybridization
    AD
    Alzheimer disease
    CI
    confidence interval
    CN
    copy number
    CNV
    copy number variant
    DZ
    dizygotic
    FISH
    fluorescent in situ hybridization
    HR
    hazard ratio
    LD
    linkage disequilibrium
    MLPA
    multiplex ligation-dependent probe amplification
    MZ
    monozygotic
    OR
    odds ratio
    RR
    relative risk
    SNP
    single nucleotide polymorphism.

  • Received July 20, 2010.
  • Accepted December 22, 2010.
  • Copyright © 2011 by AAN Enterprises, Inc.
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