Ronald M. Loeb Center for Alzheimer's Disease, Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Genet. 2018 Nov;50(11):1584-1592. doi: 10.1038/s41588-018-0238-1. Epub 2018 Oct 8.
Here we use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLPFC) of 450 subjects from two aging cohorts. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer's disease. We also generate a catalog of splicing quantitative trait loci (sQTL) effects: splicing of 3,006 genes is influenced by genetic variation. We report that altered splicing is the mechanism for the effects of the PICALM, CLU and PTK2B susceptibility alleles. Furthermore, we performed a transcriptome-wide association study and identified 21 genes with significant associations with Alzheimer's disease, many of which are found in known loci, whereas 8 are in novel loci. These results highlight the convergence of old and new genes associated with Alzheimer's disease in autophagy-lysosomal-related pathways. Overall, this study of the transcriptome of the aging brain provides evidence that dysregulation of mRNA splicing is a feature of Alzheimer's disease and is, in some cases, genetically driven.
在这里，我们使用深度测序来鉴定两个衰老队列的 450 名受试者的背外侧前额叶皮层 (DLPFC) 中 mRNA 剪接的变异来源。数以百计的异常前体 mRNA 剪接事件与阿尔茨海默病具有可重复性。我们还生成了剪接数量性状基因座 (sQTL) 效应的目录：3006 个基因的剪接受到遗传变异的影响。我们报告说，剪接是 PICALM、CLU 和 PTK2B 易感性等位基因作用的机制。此外，我们进行了全转录组关联研究，鉴定出 21 个与阿尔茨海默病有显著关联的基因，其中许多基因位于已知的基因座，而 8 个位于新的基因座。这些结果突出了与阿尔茨海默病相关的自噬溶酶体相关途径中旧基因和新基因的趋同。总的来说，这项对衰老大脑转录组的研究提供了证据，表明 mRNA 剪接的失调是阿尔茨海默病的一个特征，在某些情况下是由遗传驱动的。
