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

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, Amy K. Y. Fu, Yun Li and Nancy Y. Ip ()
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Xiaopu Zhou: The Hong Kong University of Science and Technology
Yu Chen: The Hong Kong University of Science and Technology
Kin Y. Mok: The Hong Kong University of Science and Technology
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
Yuewen Chen: The Hong Kong University of Science and Technology
Nandita Mullapudi: The Hong Kong University of Science and Technology
Paola Giusti-Rodríguez: University of North Carolina
Patrick F. Sullivan: University of North Carolina
John Hardy: University College London Institute of Neurology
Amy K. Y. Fu: The Hong Kong University of Science and Technology
Yun Li: University of North Carolina
Nancy Y. Ip: The Hong Kong University of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10945-z

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