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Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease

Author

Listed:
  • Herve Rhinn

    (Cell Biology, and Neurology, Columbia University, 650 W. 168th Street, New York, New York 10032, USA
    Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, 650 W. 168th Street, New York, New York 10032, USA)

  • Ryousuke Fujita

    (Cell Biology, and Neurology, Columbia University, 650 W. 168th Street, New York, New York 10032, USA
    Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, 650 W. 168th Street, New York, New York 10032, USA)

  • Liang Qiang

    (Cell Biology, and Neurology, Columbia University, 650 W. 168th Street, New York, New York 10032, USA
    Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, 650 W. 168th Street, New York, New York 10032, USA)

  • Rong Cheng

    (Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, 650 W. 168th Street, New York, New York 10032, USA)

  • Joseph H. Lee

    (Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, 650 W. 168th Street, New York, New York 10032, USA
    Columbia University, 630 W. 168th Street, New York, New York 10032, USA)

  • Asa Abeliovich

    (Cell Biology, and Neurology, Columbia University, 650 W. 168th Street, New York, New York 10032, USA
    Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, 650 W. 168th Street, New York, New York 10032, USA)

Abstract

Late-onset Alzheimer’s disease (LOAD) risk is strongly influenced by genetic factors such as the presence of the apolipoprotein E ε4 allele (referred to here as APOE4), as well as non-genetic determinants including ageing. To pursue mechanisms by which these affect human brain physiology and modify LOAD risk, we initially analysed whole-transcriptome cerebral cortex gene expression data in unaffected APOE4 carriers and LOAD patients. APOE4 carrier status was associated with a consistent transcriptomic shift that broadly resembled the LOAD profile. Differential co-expression correlation network analysis of the APOE4 and LOAD transcriptomic changes identified a set of candidate core regulatory mediators. Several of these—including APBA2, FYN, RNF219 and SV2A—encode known or novel modulators of LOAD associated amyloid beta A4 precursor protein (APP) endocytosis and metabolism. Furthermore, a genetic variant within RNF219 was found to affect amyloid deposition in human brain and LOAD age-of-onset. These data implicate an APOE4 associated molecular pathway that promotes LOAD.

Suggested Citation

  • Herve Rhinn & Ryousuke Fujita & Liang Qiang & Rong Cheng & Joseph H. Lee & Asa Abeliovich, 2013. "Integrative genomics identifies APOE ε4 effectors in Alzheimer's disease," Nature, Nature, vol. 500(7460), pages 45-50, August.
    • Handle: RePEc:nat:nature:v:500:y:2013:i:7460:d:10.1038_nature12415
    DOI: 10.1038/nature12415
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