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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
Xiaopu Zhou1, Yu Chen1,2,3, Kin Y Mok1,4
1Division 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.
Nature Communications
|July 27, 2019
Summary
New Alzheimer's disease (AD) risk factors have been identified near the APOE gene. These genetic variations, independent of APOE-ε4, influence cognitive function and gene expression, offering new insights into AD pathogenesis.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Alzheimer's disease (AD) is a major cause of death in older adults.
- The APOE-ε4 variant is a known major risk factor for late-onset AD.
- However, APOE-ε4 alone does not fully account for the genetic risk associated with the APOE locus.
Purpose of the Study:
- To identify novel AD causal variants within the APOE locus.
- To define risk haplotypes in the APOE region independent of the APOE-ε4 coding change.
- To investigate the impact of these risk haplotypes on AD-related endophenotypes and gene expression.
Main Methods:
- Genome-wide association studies (GWAS) to identify AD causal variants.
- Haplotype analysis to define risk haplotypes.
- Analysis of cognitive performance and gene expression (APOE and nearby genes) in human brain and blood.
- High-throughput genome-wide chromosome conformation capture (Hi-C) to assess chromatin states and gene regulation.
Main Results:
- Identification of AD causal variants in the PVRL2 and APOC1 regions near APOE.
- Definition of common risk haplotypes independent of APOE-ε4 coding change.
- Association of these risk haplotypes with altered cognitive performance and gene expression of APOE and neighboring genes in brain and blood.
- Hi-C data confirmed the role of risk haplotypes in modulating chromatin structure and gene expression in the brain.
Conclusions:
- The APOE locus harbors additional risk factors for Alzheimer's disease beyond the APOE-ε4 coding variant.
- These novel risk haplotypes contribute to AD pathogenesis by influencing cognitive function and gene expression.
- These findings expand our understanding of the genetic architecture of AD within the critical APOE region.