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首页> 外文期刊>Alzheimer s Research & Therapy >Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease
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Genome-wide pleiotropy analysis of neuropathological traits related to Alzheimer’s disease

机译：全基因组多效性分析与阿尔茨海默氏病有关的神经病理学特征

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Simultaneous consideration of two neuropathological traits related to Alzheimer’s disease (AD) has not been attempted in a genome-wide association study. We conducted genome-wide pleiotropy analyses using association summary statistics from the Beecham et al. study (PLoS Genet 10:e1004606, 2014) for AD-related neuropathological traits, including neuritic plaque (NP), neurofibrillary tangle (NFT), and cerebral amyloid angiopathy (CAA). Significant findings were further examined by expression quantitative trait locus and differentially expressed gene analyses in AD vs. control brains using gene expression data. Genome-wide significant pleiotropic associations were observed for the joint model of NP and NFT (NP + NFT) with the single-nucleotide polymorphism (SNP) rs34487851 upstream of C2orf40 (alias ECRG4, P = 2.4 × 10?8) and for the joint model of NFT and CAA (NFT + CAA) with the HDAC9 SNP rs79524815 (P = 1.1 × 10?8). Gene-based testing revealed study-wide significant associations (P ≤ 2.0 × 10?6) for the NFT + CAA outcome with adjacent genes TRAPPC12, TRAPPC12-AS1, and ADI1. Risk alleles of proxy SNPs for rs79524815 were associated with significantly lower expression of HDAC9 in the brain (P = 3.0 × 10?3), and HDAC9 was significantly downregulated in subjects with AD compared with control subjects in the prefrontal (P = 7.9 × 10?3) and visual (P = 5.6 × 10?4) cortices. Our findings suggest that pleiotropy analysis is a useful approach to identifying novel genetic associations with complex diseases and their endophenotypes. Functional studies are needed to determine whether ECRG4 or HDAC9 is plausible as a therapeutic target.
机译：在全基因组关联研究中，尚未尝试同时考虑与阿尔茨海默氏病（AD）相关的两个神经病理学特征。我们使用Beecham等人的关联摘要统计数据进行了全基因组多效性分析。研究（PLoS Genet 10：e1004606，2014）研究与AD相关的神经病理学特征，包括神经性斑块（NP），神经原纤维缠结（NFT）和脑淀粉样血管病（CAA）。通过表达定量性状基因座和使用基因表达数据在AD与对照脑中差异表达的基因分析进一步检查了重要发现。在NP和NFT的联合模型（NP + NFT）与C2orf40上游的单核苷酸多态性（SNP）rs34487851（别名ECRG4，P = 2.4×10？8）的联合基因组中观察到全基因组显着的多效性关联。 HDAC9 SNP rs79524815（P = 1.1×10？8）的NFT和CAA（NFT + CAA）模型。基于基因的测试显示NFT + CAA结果与相邻基因TRAPPC12，TRAPPC12-AS1和ADI1在研究范围内具有显着关联（P≤2.0×10？6）。 rs79524815的代理SNP的风险等位基因与大脑中HDAC9的表达显着降低有关（P = 3.0×10？3），AD患者的HDAC9与前额叶中的对照对象相比显着下调（P = 7.9×10 ？3）和视觉（P = 5.6×10？4）皮质。我们的研究结果表明，多效性分析是一种鉴定与复杂疾病及其内表型有关的新型遗传关联的有用方法。需要进行功能研究以确定ECRG4或HDAC9是否可以作为治疗靶点。

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