Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility. (November 2018)

• Record Type: Journal Article
• Authors: Raj, Towfique; Li, Yang; Wong, Garrett; Humphrey, Jack; Wang, Minghui; Ramdhani, Satesh; Wang, Ying-Chih; Ng, Bernard; Gupta, Ishaan; Haroutunian, Vahram; Schadt, Eric; Young-Pearse, Tracy; Mostafavi, Sara; Zhang, Bin; Sklar, Pamela; Bennett, David; De Jager, Philip
• Is Part Of: Nature genetics. Volume 50:Number 11(2018)
• Page Start: 1584
• Page End: 1592
• Publication Date: 2018-11
• Subjects: Human genetics -- Periodicals; 576.505
• DOI: 10.1038/s41588-018-0238-1
• Languages: English
• ISSNs: 1061-4036

Abstract

Abstract 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 thePICALM, CLU andPTK2B 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. Analysis of mRNA splicing in the dorsolateral prefrontal cortex from two cohorts established to study aging identifies variations in pre-mRNA splicing events that are associated with Alzheimer's disease.