Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
Cell Syst. 2017 Aug 23;5(2):140-148.e2. doi: 10.1016/j.cels.2017.06.016. Epub 2017 Aug 16.
Linking putatively pathogenic variants to the tissues they affect is necessary for determining the correct diagnostic workup and therapeutic regime in undiagnosed patients. Here, we explored how gene expression across healthy tissues can be used to infer this link. We integrated 6,665 tissue-wide transcriptomes with genetic disorder knowledge bases covering 3,397 diseases. Receiver-operating characteristics (ROC) analysis using expression levels in each tissue and across tissues indicated significant but modest associations between elevated expression and phenotype for most tissues (maximum area under ROC curve = 0.69). At extreme elevation, associations were marked. Upregulation of disease genes in affected tissues was pronounced for genes associated with autosomal dominant over recessive disorders. Pathways enriched for genes expressed and associated with phenotypes highlighted tissue functionality, including lipid metabolism in spleen and DNA repair in adipose tissue. These results suggest features useful for evaluating the likelihood of particular tissue manifestations in genetic disorders. The web address of an interactive platform integrating these data is provided.
将疑似致病性变异与受其影响的组织联系起来，对于确定未确诊患者的正确诊断方法和治疗方案是必要的。在这里，我们探讨了如何利用健康组织中的基因表达来推断这种联系。我们整合了 6665 个全组织转录组和涵盖 3397 种疾病的遗传疾病知识库。使用每个组织和整个组织中的表达水平进行接收者操作特征（ROC）分析表明，对于大多数组织，表达水平升高与表型之间存在显著但适度的关联（ROC 曲线下面积的最大值为 0.69）。在极端升高的情况下，关联更为明显。与常染色体显性遗传疾病相关的基因在受影响的组织中上调表达，而与常染色体隐性遗传疾病相关的基因则下调表达。与表型相关的表达基因富集的途径突出了组织功能，包括脾脏中的脂质代谢和脂肪组织中的 DNA 修复。这些结果表明，这些特征对于评估遗传疾病中特定组织表现的可能性有用。提供了一个整合这些数据的交互式平台的网络地址。
