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The integrated landscape of causal genes and pathways in schizophrenia

机译:精神分裂症因果基因和途径的整合景观

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Genome-wide association studies (GWAS) have identified more than 100 loci that show robust association with schizophrenia risk. However, due to the complexity of linkage disequilibrium and gene regulatory, it is challenging to pinpoint the causal genes at the risk loci and translate the genetic findings from GWAS into disease mechanism and clinical treatment. Here we systematically predicted the plausible candidate causal genes for schizophrenia at genome-wide level. We utilized different approaches and strategies to predict causal genes for schizophrenia, including Sherlock , SMR, DAPPLE, Prix Fixe , NetWAS , and DEPICT . By integrating the results from different prediction approaches, we identified six top candidates that represent promising causal genes for schizophrenia, including CNTN4, GATAD2A, GPM6A, MMP16, PSMA4 , and TCF4 . Besides, we also identified 35 additional high-confidence causal genes for schizophrenia. The identified causal genes showed distinct spatio-temporal expression patterns in developing and adult human brain. Cell-type-specific expression analysis indicated that the expression level of the predicted causal genes was significantly higher in neurons compared with oligodendrocytes and microglia ( P
机译:全基因组关联研究(GWAS)已鉴定出100多个位点,这些位点与精神分裂症的风险密切相关。但是,由于连锁不平衡和基因调控的复杂性,将因果基因精确定位在风险基因座并将GWAS的遗传发现转化为疾病机制和临床治疗具有挑战性。在这里,我们在全基因组水平上系统地预测了精神分裂症的可能候选病因基因。我们采用了不同的方法和策略来预测精神分裂症的病因基因,包括Sherlock,SMR,DAPPLE,Prix Fixe,NetWAS和DEPICT。通过整合来自不同预测方法的结果,我们确定了六个最有可能代表精神分裂症的有因果基因的候选基因,包括CNTN4,GATAD2A,GPM6A,MMP16,PSMA4和TCF4。此外,我们还发现了另外35个精神分裂症的高信因基因。所确定的因果基因在发育中的和成年的人脑中显示出独特的时空表达模式。细胞类型特异性表达分析表明,与少突胶质细胞和小胶质细胞相比,预测的致病基因在神经元中的表达水平明显更高(P <?0.05)。我们发现,在确定的病因基因中,突触传递相关基因显着富集(P <?0.05),为精神分裂症中突触传递的失调提供了进一步的支持。最后,我们显示精神分裂症病例中与对照组相比,前六个因果基因失调,而敲除这些基因会损害神经元细胞的增殖。我们的研究首次描述了合理的精神分裂症因果基因的格局。这些基因的进一步遗传和功能验证将为精神分裂症的发病机理提供机制方面的见解,并可能有助于为将来的治疗和诊断提供潜在的靶标。

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