一种常见的单倍型会降低髓系细胞中PU.1的表达，并延缓阿尔茨海默病的发病。
A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.
作者信息
Huang Kuan-Lin, Marcora Edoardo, Pimenova Anna A, Di Narzo Antonio F, Kapoor Manav, Jin Sheng Chih, Harari Oscar, Bertelsen Sarah, Fairfax Benjamin P, Czajkowski Jake, Chouraki Vincent, Grenier-Boley Benjamin, Bellenguez Céline, Deming Yuetiva, McKenzie Andrew, Raj Towfique, Renton Alan E, Budde John, Smith Albert, Fitzpatrick Annette, Bis Joshua C, DeStefano Anita, Adams Hieab H H, Ikram M Arfan, van der Lee Sven, Del-Aguila Jorge L, Fernandez Maria Victoria, Ibañez Laura, Sims Rebecca, Escott-Price Valentina, Mayeux Richard, Haines Jonathan L, Farrer Lindsay A, Pericak-Vance Margaret A, Lambert Jean Charles, van Duijn Cornelia, Launer Lenore, Seshadri Sudha, Williams Julie, Amouyel Philippe, Schellenberg Gerard D, Zhang Bin, Borecki Ingrid, Kauwe John S K, Cruchaga Carlos, Hao Ke, Goate Alison M
机构信息
Department of Medicine and McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, Missouri, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York,New York, USA.
出版信息
Nat Neurosci. 2017 Aug;20(8):1052-1061. doi: 10.1038/nn.4587. Epub 2017 Jun 19.
A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.
对14406例阿尔茨海默病（AD）病例和25849例对照进行的全基因组生存分析，确定了8个先前报道的AD风险位点以及14个与发病年龄相关的新位点。对220种细胞类型的连锁不平衡评分回归表明，髓系基因表达调控与AD风险有关。先前报道的CELF1 AD风险位点内的rs1057233（G）次要等位基因，与AD发病延迟以及单核细胞和巨噬细胞中SPI1表达降低有关。SPI1编码PU.1，这是一种对髓系细胞发育和功能至关重要的转录因子。AD遗传力在PU.1顺反组中富集，提示AD中存在髓系PU.1靶基因网络。最后，实验性改变PU.1水平影响了许多AD风险基因的小鼠直系同源基因的表达以及小鼠小胶质细胞的吞噬活性。我们的结果表明，较低的SPI1表达通过调节髓系基因表达和细胞功能降低AD风险。
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