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.
Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development, HKUST Shenzhen Research Institute, 518057, Shenzhen, Guangdong, China.
Nat Commun. 2019 Jul 25;10(1):3310. doi: 10.1038/s41467-019-10945-z.
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.
阿尔茨海默病（AD）是老年人死亡的主要原因。虽然 APOE-ε4 的编码变化是晚发性 AD 的关键风险因素，并且一直被认为是 APOE 基因座中的唯一风险因素，但它并不能完全解释该基因座所赋予的风险效应。在这里，我们报告了在 APOE 附近的 PVRL2 和 APOC1 区域中 AD 因果变异的鉴定，并定义了与 APOE-ε4 编码变化无关的常见风险单倍型。这些风险单倍型与 AD 相关的表型变化有关，包括认知表现，以及人类大脑和血液中 APOE 及其附近基因的表达改变。高通量全基因组染色体构象捕获分析进一步支持了这些风险单倍型在调节大脑中染色质状态和基因表达中的作用。我们的研究结果为 APOE 基因座中导致 AD 发病机制的其他风险因素提供了有力证据。
