Non-coding variability at the APOE locus contributes to the Alzheimer's risk
Non-coding variability at the APOE locus contributes to the Alzheimer's risk
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APOE 位点的非编码变异会增加阿尔茨海默病的风险
DOI：
10.1038/s41467-019-10945-z
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发表时间：
2019
影响因子：
16.6
通讯作者：
Ip Nancy Y.
中科院分区：
文献类型：
--
作者：
Zhou Xiaopu;Yu Chen;Mok Kin Y.;Kwok Timothy C. Y.;Mok Vincent C. T.;Guo Qihao;Ip Fanny C.;Chen Yuewen;Mullapudi N;ita;Giusti-Rodriguez Paola;Sullivan Patrick F.;Hardy John;Fu Amy K. Y.;Li Yun;Ip Nancy Y.
阿尔茨海默病（AD）是老年人死亡的主要原因。虽然apoe -ε4的编码改变是迟发性AD的关键危险因素，并且被认为是apoelocus中唯一的危险因素，但它并不能完全解释该位点所赋予的风险效应。在这里，我们报告了在靠近apoe的pvrl2和apoc1区域发现AD的致病变异，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相关的内表型变化有关，包括认知能力，以及人类大脑和血液中apoe及其附近基因表达的改变。高通量全基因组染色体构象捕获分析进一步支持这些风险单倍型在调节大脑染色质状态和基因表达中的作用。我们的研究结果提供了令人信服的证据，证明apoelocus中的其他危险因素有助于AD的发病机制。
Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change ofAPOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in theAPOElocus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants inPVRL2andAPOC1regions in proximity toAPOEand define common risk haplotypes independent ofAPOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression ofAPOEand 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 theAPOElocus that contribute to AD pathogenesis.