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; Nancy Y Ip; Alzheimer’s Disease Neuroimaging Initiative

doi:10.1038/s41467-019-10945-z

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.10(1), 3310

07/25/2019

DOI: 10.1038/s41467-019-10945-z

PMCID: PMC6658518

PMID: 31346172

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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.

Gene Expression

Aged

Aged, 80 and over

Alzheimer Disease - genetics

Alzheimer Disease - metabolism

Alzheimer Disease - psychology

Apolipoproteins C - genetics

Apolipoproteins C - metabolism

Apolipoproteins E - genetics

Apolipoproteins E - metabolism

Brain - metabolism

Case-Control Studies

Cognition

Female

Genetic Predisposition to Disease

Genetic Variation

Haplotypes

Humans

Male

Middle Aged

Nectins - genetics

Nectins - metabolism

Polymorphism, Single Nucleotide

Details

Title: Subtitle: Non-coding variability at the APOE locus contributes to the Alzheimer's risk
Creators: Xiaopu Zhou - Hong Kong University of Science and Technology
Yu Chen - The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, 518055, Shenzhen, Guangdong, China
Kin Y Mok - Department of Molecular Neuroscience, University College London Institute of Neurology, London, WC1N 3BG, UK
Timothy C Y Kwok - Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Vincent C T Mok - Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Qihao Guo - Department of Neurology, Huashan Hospital, Fudan University, 200040, Shanghai, China
Fanny C Ip - Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, 518057, Shenzhen, Guangdong, China
Yuewen Chen - The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, 518055, Shenzhen, Guangdong, China
Nandita Mullapudi - Division of Life Science, State Key Laboratory of Molecular Neuroscience and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
Paola Giusti-Rodríguez - Department of Genetics, University of North Carolina, Chapel Hill, NC, USA, 27599
Patrick F Sullivan - Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA, 27599
John Hardy - University College London
Amy K Y Fu - Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, 518057, Shenzhen, Guangdong, China
Yun Li - Department of Biostatistics and Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA, 27599
Nancy Y Ip - Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, 518057, Shenzhen, Guangdong, China. boip@ust.hk
Alzheimer’s Disease Neuroimaging Initiative
Contributors: HyungSub Shim (Contributor) - University of Iowa, Neurology
Resource Type: Journal article
Publication Details: Nature communications, Vol.10(1), 3310
DOI: 10.1038/s41467-019-10945-z
PMID: 31346172
PMCID: PMC6658518
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: G-0907 / Parkinson's UK MR/N026004/1 / Medical Research Council G0701075 / Medical Research Council G0901254 / Medical Research Council MR/L501542/1 / Medical Research Council P30 AG010124 / NIA NIH HHS UL1 TR002369 / NCATS NIH HHS MR/K01417X/1 / Medical Research Council
Language: English
Date published: 07/25/2019
Academic Unit: Neurology; Psychiatry
Record Identifier: 9984303026402771

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