Sassi Celeste, Ridge Perry G, Nalls Michael A, Gibbs Raphael, Ding Jinhui, Lupton Michelle K, Troakes Claire, Lunnon Katie, Al-Sarraj Safa, Brown Kristelle S, Medway Christopher, Lord Jenny, Turton James, Morgan Kevin, Powell John F, Kauwe John S, Cruchaga Carlos, Bras Jose, Goate Alison M, Singleton Andrew B, Guerreiro Rita, Hardy John
Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
PLoS One. 2016 Jun 1;11(6):e0150079. doi: 10.1371/journal.pone.0150079. eCollection 2016.
The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4<p-value<0.05), were found to be rare coding variants (0.009%<MAF<1.4%) with moderate to strong effect size (1.84<OR<Inf) that map to genes mainly involved in Aβ extracellular degradation (TTR, ACE), clearance (LRP1) and APP trafficking and recycling (SORL1). These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests), that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 <p-value <0.05). In concert with previous studies, we suggest that 1) common coding variability in APP-Aβ genes is not a critical factor for AD development and 2) Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD.
淀粉样前体蛋白（APP）的神经毒性蛋白水解衍生物Aβ42在大脑中的沉积是阿尔茨海默病（AD）（淀粉样蛋白假说）的核心事件。鉴于APP - Aβ代谢在AD发病机制中的关键作用，我们选择了29个参与APP加工、Aβ降解和清除的基因。然后，我们使用外显子组和基因组测序来研究这些基因中编码变异作为AD潜在易感因素的单一独立效应（单变异关联测试）和累积效应（基于基因的关联测试），该队列由332例散发性且主要为晚发性AD病例以及来自北美和英国的676名老年对照组成。我们的研究表明，这些基因中的常见编码变异在疾病发展中不起主要作用。在单变异关联分析中，主要的关联结果在多重检验校正后均无统计学意义（1.9e - 4 < p值 < 0.05），发现是罕见的编码变异（0.009% < 最小等位基因频率 < 1.4%），其效应大小为中度至强（1.84 < 比值比 < ∞），这些变异映射到主要参与Aβ细胞外降解（TTR、ACE）、清除（LRP1）以及APP运输和再循环（SORL1）的基因。这些结果在基于基因的分析（c - alpha和SKAT测试）中得到了部分重复，该分析报告ECE1、LYZ和TTR与AD名义上相关（1.7e - 3 < p值 < 0.05）。与先前的研究一致，我们认为：1）APP - Aβ基因中的常见编码变异不是AD发展的关键因素；2）Aβ降解和清除而非Aβ产生可能在散发性AD的病因中起关键作用。
