Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer’s disease susceptibility

• Published in: Nature genetics Vol. 50; no. 11; pp. 1584 - 1592
• Main Authors: Raj, Towfique, Li, Yang I., Wong, Garrett, Humphrey, Jack, Wang, Minghui, Ramdhani, Satesh, Wang, Ying-Chih, Ng, Bernard, Gupta, Ishaan, Haroutunian, Vahram, Schadt, Eric E., Young-Pearse, Tracy, Mostafavi, Sara, Zhang, Bin, Sklar, Pamela, Bennett, David A., De Jager, Philip L.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2018; Nature Publishing Group
• Subjects: 38; 38/39; 38/43; 631/208/191/2018; 631/208/212/2019; 692/699/375; Aged; Aged, 80 and over; Aging; Aging (Biology); Aging - genetics; Aging - metabolism; Agriculture; Alleles; Alternative Splicing - genetics; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Analysis; Animal Genetics and Genomics; Autophagy; Binding sites; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Cancer Research; Chromosome Mapping - methods; Cohort Studies; Consortia; Disease susceptibility; DNA sequencing; Female; Gene expression; Gene Expression Profiling - methods; Gene Function; Gene loci; Gene mapping; Gene sequencing; Generalized linear models; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic research; Genome-Wide Association Study; Genomes; Genotype & phenotype; Health aspects; Human Genetics; Humans; Male; Medical schools; Memory; Messenger RNA; Mutation; Neurodegenerative diseases; Phagocytosis; Prefrontal cortex; Proteins; Quantitative genetics; Quantitative trait loci; Quantitative Trait Loci - genetics; Religious orders; RNA; RNA Splicing - genetics; Splicing; Studies; Systems Biology - methods; Systems Integration; Transcriptome - genetics; United States > US
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-018-0238-1

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. 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.