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Non-coding variability at the APOE locus contributes to the Alzheimer’s risk

Author

Listed:
  • Xiaopu Zhou

    (The Hong Kong University of Science and Technology)

  • Yu Chen

    (The Hong Kong University of Science and Technology
    HKUST Shenzhen Research Institute
    Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Kin Y. Mok

    (The Hong Kong University of Science and Technology
    University College London Institute of Neurology)

  • Timothy C. Y. Kwok

    (The Chinese University of Hong Kong)

  • Vincent C. T. Mok

    (The Chinese University of Hong Kong)

  • Qihao Guo

    (Fudan University)

  • Fanny C. Ip

    (The Hong Kong University of Science and Technology
    HKUST Shenzhen Research Institute)

  • Yuewen Chen

    (The Hong Kong University of Science and Technology
    HKUST Shenzhen Research Institute
    Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Nandita Mullapudi

    (The Hong Kong University of Science and Technology)

  • Paola Giusti-Rodríguez

    (University of North Carolina)

  • Patrick F. Sullivan

    (University of North Carolina
    Karolinska Institute
    University of North Carolina)

  • John Hardy

    (University College London Institute of Neurology)

  • Amy K. Y. Fu

    (The Hong Kong University of Science and Technology
    HKUST Shenzhen Research Institute)

  • Yun Li

    (University of North Carolina
    University of North Carolina)

  • Nancy Y. Ip

    (The Hong Kong University of Science and Technology
    HKUST Shenzhen Research Institute)

Abstract

Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.

Suggested Citation

  • Xiaopu Zhou & Yu Chen & Kin Y. Mok & Timothy C. Y. Kwok & Vincent C. T. Mok & Qihao Guo & Fanny C. Ip & Yuewen Chen & Nandita Mullapudi & Paola Giusti-Rodríguez & Patrick F. Sullivan & John Hardy & Am, 2019. "Non-coding variability at the APOE locus contributes to the Alzheimer’s risk," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10945-z
    DOI: 10.1038/s41467-019-10945-z
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