Schizophrenia hiPSC neurons display expression changes that are enriched for disease risk variants and a blunted activity-dependent response
作者： Panos Roussos , Boris Guennewig , Dominik C. Kaczorowski , Guy Barry , Kristen J. Brennand
DOI: 10.1101/062885
关键词:
摘要: IMPORTANCE: Schizophrenia (SCZ) is a common illness with complex genetic architecture where both variation and rare mutations have been implicated. SCZ candidate genes participate in molecular pathways that are regulated by activity-dependent changes neurons, including the signaling network modulates synaptic strength of targets fragile X mental retardation protein. One important next step to further our understanding on role expression etiopathogenesis SCZ. OBJECTIVE: To examine whether neuronal gene dysregulated DESIGN, SETTING, AND PARTICIPANTS: Neurons differentiated from human induced pluripotent stem cells (hiPSCs) derived 4 cases unaffected controls were depolarized using potassium chloride. RNA was extracted followed genome-wide profiling transcriptome. MAIN OUTCOMES MEASURES: We performed differential analysis co-expression identify or disease-specific Further, we used set analyses co-expressed modules enriched for risk genes. RESULTS: identified 1,669 significantly different SCZ-associated vs. control hiPSC-derived neurons 1,199 altered these response depolarization. show effect attenuated compared controls. Furthermore, differentially expressed highly affected variants other neurodevelopmental disorders. CONCLUSIONS RELEVANCE: Our results converge networks associated blunted neurons. Overall, findings hiPSC demonstrate transcriptional can be utilized underlying mechanisms therapeutic interventions related
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