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, Hong Kong University of Science and Technology Shenzhen Research Institute, Shenzhen, 518057 Guangdong, China.
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):1697-1706. doi: 10.1073/pnas.1715554115. Epub 2018 Feb 5.
Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the locus (sentinel variant rs73052335, = 1.44 × 10), two common variants, (rs72713460, = 4.36 × 10) and (rs928771, = 3.60 × 10), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the transcript can be observed in the blood of AD subjects. Moreover, the risk variants of and are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the , , and loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of and in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.
阿尔茨海默病（AD）是老年人死亡的主要原因之一。我们对中国人群的 AD 进行了全基因组测序研究。除了在 基因座内或附近鉴定出的变体（哨兵变体 rs73052335， = 1.44 × 10）外，还鉴定出了两个常见变体 （rs72713460， = 4.36 × 10）和 （rs928771， = 3.60 × 10），并在三个非亚洲 AD 小队列中进一步验证了它们对 AD 的可能风险效应。基因型-表型分析表明， 变体 rs928771 影响 AD 的发病年龄，携带次要等位基因的患者发病较早。此外，在 AD 患者的血液中可以观察到 转录本的表达水平发生改变。此外， 和 基因的风险变体与它们在特定组织中转录本水平的变化以及 AD 患者的血浆生物标志物水平的变化有关。重要的是，海马和血液转录组数据集的网络分析表明， 、 和 基因座中的风险变体可能通过对免疫相关途径的调节作用发挥其功能。综合这些数据，我们在中国人群中鉴定出了与 AD 风险相关的 和 常见变体。这些变体可能通过免疫系统发挥其功能作用。
