We use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLFPC) 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. Further, we performed a transcriptome-wide association study and identified 21 genes with significant associations to Alzheimer’s disease, many of which are found in known loci, but 8 are in novel loci. This highlights the convergence of old and new Alzheimer’s disease genes in autophagy-lysosomal-related pathways. Overall, this study of the aging brain’s transcriptome provides evidence that dysregulation of mRNA splicing is a feature of Alzheimer’s disease and is, in some cases, genetically driven.
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 Alzheimer's 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 transcriptomewide 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 brain's transcriptome provides evidence that dysregulation of mRNA splicing is a feature of AD and is, in some genetically-driven cases, causal.peer-reviewed)
Recent human genetic studies suggest that cells of the innate immune system have a primary role in the pathogenesis of neurodegenerative diseases. However, the results from these studies often do not elucidate how the genetic variants affect the biology of these cells to modulate disease risk. Here, we applied a tensor decomposition method to uncover disease-associated gene networks linked to distal genetic variation in stimulated human monocytes and macrophages gene expression profiles. We report robust evidence that some disease-associated genetic variants affect the expression of multiple genes in trans. These include a Parkinson's disease locus influencing the expression of genes mediated by a protease that controls lysosomal function, and Alzheimer's disease loci influencing the expression of genes involved in type 1 interferon signaling, myeloid phagocytosis, and complement cascade pathways. Overall, we uncover gene networks in induced innate immune cells linked to disease-associated genetic variants, which may help elucidate the underlying biology of disease.
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