RESUMO
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 monocyte and macrophage 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.
Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Modelos Genéticos , Doença de Parkinson/genética , Locos de Características Quantitativas/imunologia , Doença de Alzheimer/imunologia , Linhagem Celular , Mapeamento Cromossômico , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Variação Genética/imunologia , Estudo de Associação Genômica Ampla , Humanos , Imunidade Inata/genética , Interferon gama/imunologia , Lipopolissacarídeos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Doença de Parkinson/imunologiaRESUMO
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.