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 splici...