Abstract

We use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLFPC) of 450 subjects from two prospective cohort studies of aging. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimers Disease (AD). We also generate a catalog of splicing quantitative trait loci (sQTL) effects in the human cortex: splicing of 3,198 genes is influenced by genetic variation. sQTLs are enriched among those variants influencing DNA methylation and histone acetylation. In assessing known AD loci, we report that altered splicing is the mechanism for the effects of the PICALM, CLU, and PTK2B susceptibility alleles. Further, we leverage our sQTL catalog to identify genes whose aberrant splicing is associated with AD and mediated by genetics. This transcriptome-wide association study identified 21 genes with significant associations, many of which are found in AD GWAS loci, but 8 are in novel AD loci, including FUS, which is a known amyotrophic lateral sclerosis (ALS) gene. This highlights an intriguing shared genetic architecture that is further elaborated by the convergence of old and new AD genes in autophagy-lysosomal-related pathways already implicated in AD and other neurodegenerative diseases. Overall, this study of the aging brains transcriptome provides evidence that dysregulation of mRNA splicing is a feature of AD and is, in some genetically-driven cases, causal.