Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease
Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease
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DOI：
10.1371/journal.pone.0218111
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发表时间：
2019-07-08
期刊：
影响因子：
3.7
通讯作者：
Escott-Price, Valentina
中科院分区：
文献类型：
--
作者：
Baker, Emily;Sims, Rebecca;Escott-Price, Valentina
晚发性阿尔茨海默病是最常见的痴呆症形式，约有30个易感基因位点已被报道。当前研究的目的是利用最大的最新参考单核苷酸多态性（SNP）面板，最准确的输入软件和一种新的基于基因的分析方法来识别与阿尔茨海默病相关的新基因，该方法可以在强大的阿尔茨海默病国际基因组学项目联盟的全基因组关联数据集中测试基因内的关联模式。包括来自17,008例阿尔茨海默病病例和37,154例对照的700多万个基因型。除了先前报道的基因外，我们还检测到三个新的全基因显著位点PPARGC1A (p = 2.2 × 10(-6)), RORA （p = 7.4 × 10(-7)）和ZNF423 （p = 2.1 × 10(-6)）。PPARGC1A和RORA参与昼夜节律；昼夜节律紊乱是阿尔茨海默病的早期症状之一。PPARGC1A还与能量代谢和β淀粉样蛋白斑块的产生有关。除了昼夜节律外，RORA还参与多种功能，如胆固醇代谢和炎症。ZNF423基因位于阿尔茨海默病特异性蛋白网络中，可能与中心体和DNA损伤修复有关。
Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 x 10(-6)), RORA (p = 7.4 x 10(-7)) and ZNF423 (p = 2.1 x 10(-6)). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.